Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

Page 1 of 73 Diabetes

Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis

Jacqueline A. Koehler1, Laurie L. Baggio1, Xiemin Cao1, Tahmid Abdulla1, Jonathan E. Campbell, Thomas Secher2, Jacob Jelsing2, Brett Larsen1, Daniel J. Drucker1

From the1 Department of Medicine, TanenbaumLunenfeld Research Institute, Mt. Sinai Hospital and 2Gubra, Hørsholm, Denmark

Running title: GLP1 increases pancreatic protein synthesis

Key Words: glucagonlike peptide 1, glucagonlike peptide1 receptor, incretin, exocrine pancreas

Word Count 4,000 Figures 4 Tables 1

Address correspondence to:

Daniel J. Drucker M.D.

LunenfeldTanenbaum Research Institute

Mt. Sinai Hospital 600 University Ave TCP51004

Toronto Ontario Canada M5G 1X5

4163612661 V 4163612669 F [email protected]

Diabetes Publish Ahead of Print, published online October 2, 2014 Diabetes Page 2 of 73

Abstract

Glucagonlike peptide1 (GLP1) controls glucose homeostasis by regulating secretion of insulin

and glucagon through a single GLP1 receptor (GLP1R). GLP1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we

demonstrate that the increase in pancreatic weight following activation of GLP1R signaling in

mice reflects an increase in acinar cell mass, without changes in ductal compartments or βcell

mass. GLP1R agonists did not increase pancreatic DNA content or the number of Ki67+ cells in

the exocrine compartment, however pancreatic protein content was increased in mice treated

with exendin4 or liraglutide. The increased pancreatic mass and protein content was

independent of cholecystokinin receptors, associated with a rapid increase in S6 kinase phosphorylation, and mediated through the GLP1 receptor. Rapamycin abrogated the GLP1R

dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and

Reg3β gene expression. Mass spectrometry analysis identified GLP1Rdependent upregulation of proteins important for translation, and export, including cytochrome P450, Fam129a, eIF4a1,

Wars, and Dmbt1. Hence, pharmacological GLP1R activation induces protein synthesis leading to increased pancreatic mass independent of changes in DNA content or cell proliferation in mice.

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Gut hormones secreted from specialized endocrine cells subserve multiple functions integrating

control of food ingestion, gut motility, and the digestion, absorption and assimilation of

nutrients. The actions of enteroendocrine peptides to control lipid metabolism, body weight and

glucose homeostasis have engendered considerable translational interest given the increasing

incidence of dyslipidemia, obesity and diabetes. Glucagonlike peptide1 (GLP1), secreted from

enteroendocrine L cells, reduces food intake, inhibits gastric emptying, and produces weight loss.

GLP1 also inhibits chylomicron secretion from enterocytes and lowers triglyceride levels in

both preclinical and clinical studies (1). The most extensively studied action of GLP1 is that of

an incretin hormone, augmenting insulin and inhibiting glucagon secretion following meal

ingestion, through actions targeting endocrine cells in the pancreas. Collectively, the

glucoregulatory actions of incretin hormones led to development of two distinct drug classes that

lower glucose by potentiation of incretin action, dipeptidyl peptidase4 (DPP4) inhibitors, and

GLP1 receptor (GLP1R) agonists (2).

Although classical glucoregulatory actions of incretinbased therapies target the endocrine

pancreas, the nonglycemic actions of GLP1R agonists and DPP4 inhibitors on the exocrine

pancreas have received considerable attention (3). Spontaneous reports of pancreatitis in diabetic

patients treated with incretinbased therapies stimulated interest in whether GLP1R agonists

affect the exocrine pancreas (4). Although results of preclinical studies are conflicting, the

majority of experiments do not link activation of GLP1R signaling to enhanced susceptibility to

pancreatitis in rodents (4; 5). Furthermore studies of transgenic reporter gene expression under

the control of the endogenous murine Glp1r promoter (6), have not demonstrated GLP1R

expression in pancreatic acinar cells.

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Despite lack of evidence for GLP1R expression in acinar cells of the rodent pancreas, several preclinical studies have demonstrated that GLP1R agonists increase the mass of the pancreas, predominantly in mice (7; 8) and in a subset of male nonhuman primates (9). Nevertheless, the

increase in pancreatic weight following treatment with GLP1R agonists has not been associated

with histological abnormalities in the pancreas (3; 9; 10), and mechanistic explanations for

changes in pancreatic mass have not been forthcoming. We show here that exendin4 and

liraglutide increase pancreatic weight via induction of protein synthesis, without changes in

acinar cell proliferation or DNA content. These actions were independent of receptors for

cholecystokinin, required the classical Glp1r, and were abrogated by inhibition of the

mammalian target of rapamycin (mTor). Our findings provide an explanation for changes in pancreatic mass observed following treatment with GLP1R agonists.

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RESEARCH DESIGN AND METHODS

Reagents, Animals and Treatments:

Exendin4 (Ex4) was from Chi Scientific (Maynard, MA), liraglutide was from Novo

Nordisk (Bagsværd, Denmark), rapamycin (Rapamune) was from Wyeth (Montreal, Quebec).

Peptides were dissolved in phosphate buffered saline (PBS, vehicle) and administered to mice by

intraperitoneal (ip) injection (Ex4;10 nmol/kg, BID, or liraglutide;75 g/kg, BID). Rapamycin

was resuspended in 0.5% carboxymethacellulose (Sigma, C4888), 2.5% tween80. C57BL/6J,

Cckar/, and Cckbr/ mice were from The Jackson Laboratory (Bar Harbor, ME). Whole body

Glp1r−/− mice in the C57BL/6 background (11; 12) and wildtype (WT) littermate control mice

were generated by crossing Glp1r+/− mice. Cckar/:Cckbr/ (DKO) and WT littermate control

mice were generated by crossing Cckar+/ and Cckbr+/ mice. Animal experiments were approved

by the Animal Care Committee of the Mount Sinai Hospital.

Pancreatic growth: Male C57BL/6 mice (810 weeksold) were administered exogenous

Ex4 or vehicle (PBS) for 7 days or 4 weeks. Male (not shown) and female Cckbr-/-, Cckar-/-, (7

12 weeksold) and Cckar:Cckbr-/- (DKO) (813 weeksold) and WT littermate control mice were

administered exogenous Ex4 or vehicle for 10 days. Nonfasted mice were euthanized by CO2

inhalation in the morning ~12h after the last injection) unless otherwise indicated. Time course:

male C57BL/6 mice (11 weeksold) were injected with Ex4 or vehicle every 12h and pancreata

obtained at 4 h, 12 h or 24h7 days. For the 24h7 day time points, mice were euthanized in the

morning ~12 h after the last injection). Rapamycin study: male C57BL/6 mice (810 weeksold)

were administered vehicle (0.5% carboxymethacellulose, 2.5% tween80) or rapamycin (2 mg/kg

1x daily ip) 30 min prior to the first (morning) injection of exogenous Ex4, or PBS for 3 or 7

days. High protein diet (HPD) study: HPD (AIN93M modified to contain 75% Casein,

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D1206504) and control diet (CD) AIN93M (D10012M) were from Research Diets (New

Brunswick, N.J.). Glp1r−/− and WT littermate control female mice (811 weeks old) were acclimatized to the CD for 1 week prior to being fed the HPD or CD ad libitum for 7 days.

Tissue collection, immunohistochemistry, DNA/protein and water content:

Following euthanasia, mice were weighed, blood samples collected by cardiac puncture, and serum was stored at 80°C. The pancreas was removed, weighed and cut in half lengthwise; onehalf was fixed in 10% formalin for 24h, the other half was cut into 4 equal sections from tail

(attached to spleen) to head for RNA, protein, DNA/protein content, and water content.

Immunohistochemistry and morphometry were done on 5m histological sections stained with

hematoxylin and eosin (H&E) or Ki67 (Thermo Scientific, RM9106S1, 1:2000) by standard procedures. Sections were scanned and analyzed using the Scanscope CS system (Aperio

Technologies) at x20 magnification. Immunohistochemistry for phosphoS6 ribosomal protein

(Cell Signaling, Ser 240/244, D68F8 XP) was performed according to manufacturer’s instructions. Immunohistochemistry for Reg3 (antisera, 1:200 dilution, Dr. Rolf Graf, University

Hospital Zurich, Zurich, Switzerland) was performed using sodium citrate buffer pH 6.0 for antigen unmasking and overnight incubation with the Reg3 antibody. Edema was calculated following desiccation for 72 h and expressed as a percentage of wet weight (wet weightdry weight/wet weight x100). For analysis of DNA and protein content, pancreas samples were weighed, homogenized in a lysis buffer containing 0.1% Tx100, 5mM MgCl2, and sonicated for

15 sec. Protein content was measured using Bradford assay (BioRad) and a Pierce BCA protein assay kit (Thermo Scientific) and DNA content was measured using a DNA quantification kit

(Sigma, DNAQF).

Serum amylase and lipase levels:

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Serum amylase activity was measured using the Phadebas amylase test (Magle Life

Sciences, Cambridge, MA) and serum lipase activity was analyzed with the Lipase color assay

(905B, Sekisui Diagnostics, Charlottetown, PE). Serum amylase and lipase activity levels were

also measured in serum samples from mice with secretagogueinduced pancreatitis induced by

administration of five sequential hourly ip injections of caerulein, 50 g/kg body wt (8).

Quantitative histological analyses of pancreas mass:

Stereological quantification of pancreas mass was carried out in collaboration with Gubra

(Gubra ApS, Hørsholm, Denmark). Male C57BL/6 mice (1213 weeksold) were administered

exogenous Ex4 (10 nmol/kg BID, ip), liraglutide (Lira: 75 g/kg, BID, ip) or vehicle for 14

days. Male Glp1r+/+ and Glp1r-/- littermate controls (812 weeksold) were administered Ex4, or

vehicle for 14 days. Pancreata were removed en bloc in 4% formaldehyde and processed for

stereological analyses as described (13). Ductal epithelial cells were detected with a rat anti

cytokeratin 19 antibody (ck19, 1:100, Hybridoma bank, University of Iowa, TROMAIII) and

visualized with DAB. Beta cells were detected with a guineapig antiinsulin antibody (1:5000,

Dako A0564) and visualized with Novared (Vectorlabs). Nonbeta cells were detected with an

antibody cocktail consisting of rabbit antiglucagon (1:5000, Phoenix H02802), rabbit anti

somatostatin (1:7500, Dako 0566), and rabbit antipancreatic polypeptide (1:5000, Europroxima

B321) and visualized with DABNickel. Endocrine mass includes the combined mass of beta

(mass of insulin immunoreactivity) and nonbeta cells (mass of glucagon, somatostatin, and

pancreatic polypeptide immunoreactivity) inside the islets.

Islet isolation, RNA extraction and quantitative real-time RT-PCR:Pancreatic islets

were isolated as described previously (14) and incubated overnight in fresh RPMI (10% FBS,

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100 U/ml penicillin, and 100 ug/ml streptomycin). The next morning, islets were handpicked for

size and viability into 1.5mL tubes. Total RNA from whole pancreatic tissue, or islets, was

extracted using TRI Reagent (Sigma) and cDNA synthesis performed with random hexamers and

SuperScript III (Invitrogen Canada). Realtime quantitative PCR was performed on an ABI

PRISM 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA) as

described (8; 14). Relative values for mRNA transcripts were normalized to the levels of

cyclophilin (Ppia).

Western blot analysis:

Wholetissue extracts were prepared by homogenization in icecold RIPA buffer (1%

Nonidet P40, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulfate in Trisbuffered saline) supplemented with protease and phosphatase inhibitors (SigmaAldrich), 5 mmol/L sodium flouride, 5 mmol/L βglycerophosphate, and 200 mol/L sodium orthovanadate. The rabbit polyclonal antibodies phosphop70 S6K (Thr389, 9205), phosphoeIF2a (Ser51, 9721), phosphoS6 (Ser240/244, 2215), were from Cell Signaling Technologies(Beverly, MA) and used at a 1:1000 dilution, 4EBP1 (BL895) was from Bethyl Laboratories Inc (Montgomery, TX) at 1:1000 dilution, or HSP90 (BD Biosciences, no. 610418) at a 1:2000 dilution. Images were scanned using a Kodak imager (Kodak Imaging Station 4000 MMPro) and quantification was performed using Carestream Molecular Imaging software (standard edition V.5.0.2.30).

Proteomics:

Preparation of pancreas samples for proteomics was performed as described using the

Filter aided sample preparations (FASP) II protocol (15). Briefly, male C57BL/6 mice (810

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weeksold) were administered exogenous Ex4 or vehicle for 7 days (n=5), the pancreas was

removed and homogenized in 4% SDS lysis buffer (4% SDS, 100 mM Tris/HCL pH7.6, 0.1M

DTT), incubated at 98 ⁰C for 3 min, followed by brief sonication and centrifugation (5 min,

16000xg). Equal protein (250 ug) was mixed with 200 ul UA buffer (8M Urea in 0.1M Tris/HCl

pH 8.5) and loaded onto Micron YM30 filter units (Millipore), washed and incubated with

trypsin (Promega, V5111) overnight in a humidified chamber. The following day the filters were

eluted and spun, eluted samples were mixed with formic acid (final 5%) and dried (speedvac).

Samples were analyzed on the 5600 TripleTOF by data dependent acquisition (DDA)

(Supplementary Table 1).

Statistical Analysis:

Results are expressed as mean ± SE. Statistical significance was assessed by oneway or

twoway ANOVA using Bonferroni's multiple comparison post test or by unpaired Student's t

test using GraphPad Prism 5.02 (GraphPad Software; San Diego, CA). A p value < 0.05 was

considered to be statistically significant.

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Results:

To identify mechanisms linking GLP1R signaling to increases in pancreatic mass, we analyzed pancreata from WT normoglycemic mice treated with Ex4 for 1 week. Ex4 increased absolute pancreas weight and pancreas weight normalized to body weight without significantly affecting body weight (Fig. 1A, Supplementary Fig. 1AC, Supplementary Fig. 2B,C), or lung weight (Supplementary Fig. 1C). As some gastrointestinal actions of GLP1R agonists exhibit tachyphylaxis with sustained activation of GLP1R signaling (16), we treated mice with Ex4 for

4 weeks. Pancreatic weight remained significantly increased after 4 weeks of Ex4 administration, at levels comparable to those observed in Ex4treated mice after 1 week (Fig.

1B, C). The increase in pancreas weight was not due to increased water content (edema), as wet:dry pancreatic weights were comparable in control vs. Ex4treated mice (Fig. 1D).

Surprisingly, DNA content was lower, despite increased pancreatic mass, after Ex4 administration (Fig. 1D). Furthermore, no significant differences in proliferating (Ki67+) cells were detected at 4, 12, 24, or 96 hrs following administration of Ex4 (Fig. 1E). Additionally, levels of mRNA transcripts for genes regulating cell cycle progression including c-myc, cyclin

D1, cyclin D2 or the cyclindependent kinase inhibitor p21cip (Supplementary Fig. 2E,F) were significantly lower (c-myc, cyclin D1, p21cip) or unchanged (cyclin D2) following Ex4 administration. In contrast, protein content, and the protein:DNA ratio was significantly increased in the pancreas of Ex4treated mice (Fig. 1D, Supplementary Fig. 2D). An increase in pancreatic mass was also detected following administration of the GLP1R agonist, liraglutide

(Fig. 1F). Although acinar cells in the murine exocrine pancreas do not express the Glp1r (6), stereological quantification revealed that the increase in pancreas mass following Ex4 or liraglutide was due to an increase in the mass of the exocrine pancreas (Fig. 1F). In contrast, no

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significant changes in relative proportions of endocrine, βcell, ductal or nonβcell

compartments were detected in mice treated with Ex4 or liraglutide (Supplementary Fig. 1D).

Consistent with the essential role for the canonical GLP1R in transducing the metabolic and

glucoregulatory actions of GLP1R agonists in mice (12; 17), Ex4 had no effect on pancreatic or

exocrine mass in Glp1r-/- mice (Fig. 1G, Supplementary Fig. 1E).

As recent studies have linked nutrientstimulated cholecystokinin (CCK) release to

activation of GLP1 secretion (18), and CCK potently increases pancreatic protein synthesis (19),

we assessed whether the actions of GLP1R agonists to increase pancreatic mass (and protein)

required CCK receptors. Ex4 administration augmented pancreas weight similarly in mice

lacking either Cckar-/-, or Cckbr-/- or in Cckar-/-:Cckbr-/- mice lacking both CCK receptors (Fig.

2A,B). We next queried whether endogenous GLP1R signaling was required for the adaptive

increase in pancreatic mass in response to a high protein diet (20), however pancreas weight was

increased to a similar extent in high protein dietfed Glp1r+/+ vs. Glp1r-/- mice (Fig. 2C).

Analysis of key proteins controlling the initiation of protein synthesis (Fig. 3AC)

revealed that Ex4 initially reduced the phosphorylation of the 40S ribosomal subunit S6,

however a significant increase in S6 phosphorylation was detected by 12 hrs after Ex4 treatment

(Fig. 3A,C) with further robust increases evident in pancreata from mice treated with Ex4 from

27 days (Fig. 3B,C). Similar results were seen for the gamma isoform of the translational

repressor 4EBP1 (Fig. 3AC). The induction of S6 phosphorylation required the canonical GLP

1R, as S6 phosphorylation was not observed in the pancreas of Ex4treated Glp1r-/- mice (Fig.

3D). Moreover cytoplasmic staining of phosphorylated S6 was observed in acinar cells

(Supplementary Fig. 5B).

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As the mTOR pathway plays a pivotal role in the regulation of protein synthesis (21), we examined the requirement for this pathway in the GLP1Rmediated increase in pancreas weight.

Treatment with the mTOR complex 1 (mTORC1) inhibitor rapamycin had no significant effect on body weight (Supplementary Fig. 3A) but completely abolished the Ex4induced increase in pancreas weight (Fig. 3E) and S6 phosphorylation (Fig. 3G). However, the actions of Ex4 to increase small bowel mass (22) were not diminished in rapamycintreated mice (Fig. 3F).

Moreover, rapamycin did not attenuate the Ex4induction of Slc3a1, Reg3β or Reg3α nor the suppression of 21cip in the pancreas from the same experiments (Fig. 3H).

We next assessed whether activation of GLP1R signaling regulated expression of genes encoding pancreatic enzymes, as plasma levels of amylase and lipase are modestly increased in some human subjects treated with GLP1R agonists (3). Lipase mRNA levels were lower in the pancreas of Ex4treated mice, whereas levels of amylase were not significantly different (Fig.

4A,C). Consistent with these findings, serum lipase levels were reduced and amylase levels were unchanged in Ex4treated mice: however both lipase and amylase levels were markedly induced after caerulein administration (Fig. 4D). Ex4 also rapidly increased levels of pancreatic mRNA transcripts for the antiinflammatory genes socs3 and Reg3β (Fig. 4B). Socs3 mRNA transcripts returned to normal by 24h despite ongoing Ex4 administration, however Reg3β mRNA transcripts remained elevated in the pancreas of mice treated with Ex4 (Fig. 4B,C).

Furthermore, the induction of both Reg3α and Reg3β by Ex4 or liraglutide requires the GLP

1R, as neither of these transcripts were upregulated in the pancreas of Glp1r-/- mice treated with

GLP1R agonists (8; 14). Ex4 reduced levels of lipase and increased Reg3 mRNA transcripts in pancreata of rapamycintreated mice (Fig. 4E, Fig. 3H), indicating divergent mechanisms for

GLP1Rdependent control of pancreatic protein synthesis vs, gene expression. In contrast, Ex4

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did not alter levels of mRNA transcripts encoding the cationic amino acid transporter slc7a1, the

glucose transporter glut2, pyruvate dehydrogenase kinase isozyme 4 (pdk4), the exocrine

transcription factor mist1, or Cckar and Cckbr in the murine pancreas (Supplementary Fig. 3B).

To further characterize changes in the pancreatic proteome following activation of GLP

1R signaling we performed a proteomics analysis on whole pancreas tissue after 1 week of Ex4

adminstration. Spectral counting analysis was performed to identify proteins that were

specifically regulated by Ex4. The majority of proteins in the pancreas were proportionately

increased to a similar extent by Ex4 treatment (Supplementary Table 1), however some proteins

were preferentially increased or underrepresented following Ex4 administration. A summary

of the most striking differences in relative protein abundance following Ex4 treatment is shown

in Table 1, including Reg3β and Reg2 which were not detected in the pancreas of vehicletreated

mice. (Table 1, Supplementary Table 1). Similarly, fatty acid binding protein 5 (Fabp5) and

P450 cytochrome oxidoreductase (Por), proteins involved in fatty acid uptake and lipid

oxidation, were detected at low levels in the pancreas of vehicletreated mice, but were abundant

following Ex4 treatment. Other proteins upregulated by Ex4 (Table 1, Supplementary Table 1)

include those involved in protein translation and secretion, including Family with sequence

similarity 129 member A (Fam129a), eIF4a1, tryptophanyltRNA synthetase (Wars), and deleted

in malignant brain tumors 1 (Dmbt1). Notably, we did not detect upregulation of amylase or

lipase proteins after Ex4 administration (Supplementary Table 2).

An increase in protein abundance can reflect changes in both transcription and

translation, hence we examined levels of mRNA transcripts for proteins preferentially increased

by Ex4. Ex4 induced expression of the Reg genes (Reg3, Reg2, Reg1) and modestly

upregulated dmbt1 transcripts after 1 week of treatment (Fig. 3H, Fig 4B, Supplementary Fig.

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4A), whereas Reg1 and dmbt1 transcript levels were not different after 1 month of Ex4

administration (Supplementary Fig. 4B). Ex4 did not affect levels of mRNA transcripts for

many of the other Ex4induced proteins including por, fabp5, fam129a, wars or eif4a1

(Supplementary Fig. 4A,B), suggesting that the Ex4induced increase of these particular proteins was regulated at the translational level. The relative mRNA levels of reg2, reg3b, reg1, dmbt1, as well as lipase, amylase and colipase were 1001000x less abundant in RNA isolated from islets when compared with whole pancreas (Supplementary Fig. 4C) suggesting that these genes are predominantly expressed in the exocrine pancreas. These findings are consistent with predominant localization of Reg 3 protein expression to the exocrine pancreas (Supplementary

Fig. 5A). In contrast, the difference in relative mRNA levels for por, fabp5, wars and eif4a1 were not as robust in whole pancreas vs. islets, suggesting that these genes are expressed in both endocrine and exocrine compartments (Supplementary Fig. 4C). As expected, the Gcg, Glp1r, and Ins2 genes were preferentially expressed in islet RNA (Supplementary Fig. 4C).

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Discussion

Although it is often assumed that GLP1R agonists increase pancreas weight through

stimulation of exocrine cell proliferation, evidence in support of this hypothesis has not been

forthcoming (3; 4). Our findings that Ex4 or liraglutide have no effect on total endocrine cell

mass, βcell mass or the mass of ductal epithelium in normoglycemic mice are consistent with an

important role for hyperglycemia in the GLP1Rdependent stimulation of pancreatic islet cell

proliferation (7; 14; 23; 24). Indeed, some studies have reported that GLP1R agonists reduce β

cell mass in normoglycemic animals (25), possibly reflecting weight loss and increased insulin

sensitivity. A single study described increased acinar cell proliferation in chowfed mice treated

with liraglutide, however acinar cell proliferation was not increased in high fat fed mice treated

with liraglutide (25). In contrast, no significant effects of GLP1R agonists on growth and

proliferation of human pancreatic adenocarcinoma cell lines (26; 27). Hence, there is little

evidence linking activation of GLP1R signaling to the proliferation of normal or neoplastic

pancreatic acinar cells.

Levels of mRNA transcripts for the cyclindependent kinase inhibitor p21cip declined

following Ex4 administration, however a reduction in mRNA levels was also observed for genes

promoting cell cycle progression including c-myc and cyclin D2, whereas cyclin D1 remained

unchanged. Importantly, rapamycin abolished the Ex4induced increase in pancreas weight, but

did not attenuate the suppression of p21cip by Ex4, demonstrating that downregulation of

p21cip occurs independently of changes in pancreas mass. Furthermore, the number of Ki67+

cells in the exocrine compartment and total DNA content in the pancreas was not induced by Ex

4; indeed, DNA content was lower after 4 weeks of Ex4 administration, despite increased

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pancreatic mass. Taken together, it seems unlikely that GLP1R signaling promotes exocrine

cell proliferation within the context of the experimental paradigm presented herein.

While GLP1R agonists increase pancreatic mass and protein synthesis through mechanisms

requiring the known GLP1 receptor, it remains unclear how the GLP1Rdependent signal is

relayed to pancreatic acinar cells. GLP1Rdependent stimulation of insulin secretion is a logical

candidate for isletacinar communication (28), hence we studied normoglycemic mice to

minimize confounding effects of increased insulin secretion. Evidence against a role for insulin

as an indirect GLP1Rdependent stimulator of pancreatic protein synthesis and mass derives

from studies employing genetic selective restoration of hGLP1R expression in murine βcells of

Glp1r/ mice (14). Although GLP1R agonists robustly increased insulin secretion and lowered

glycemia in hGLP1R:Glp1r/ mice, Ex4 had no effect on pancreatic mass, or pancreatic expression of Reg3α or Reg3β in hGLP1R: Glp1r/ mice (14), indicating that increased levels of insulin are not sufficient to mediate the effects of GLP1R agonists on the exocrine pancreas.

CCK activates GLP1containing neurons in the central nervous system (29; 30), and GLP1 and CCK are colocalized in and secreted from subsets of enteroendocrine L cells (31).

Pancreatic growth is readily induced by CCK administration or administration of exogenous protease/trypsin inhibitors which elevate levels of CCK (32). Nevertheless, CCK agonists and protease inhibitors simultaneously induce cell proliferation and protein synthesis, whereas GLP

1R agonists increased pancreatic mass without concomitant changes in cell proliferation or DNA content. Although the overlapping actions of CCK and GLP1R agonists raised the possibility that GLP1R agonists increase pancreas mass through direct or indirect activation of CCK receptor signaling, the trophic effects of GLP1R agonists were preserved in mice with

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inactivation of one or both CCK receptors. Hence, CCK signaling is not required for the effects

of GLP1R agonists to increase pancreatic mass.

The results of our proteomic analyses demonstrate that Ex4 differentially induces the

expression of proteins involved in aspects of nutrient uptake, protein translation, protein folding,

or exocytosis. An unresolved question is whether the small increase in serum levels of lipase,

and to a lesser extent, amylase, observed in some patients treated with GLP1R agonists (3)

reflects the actions of these agents to increase pancreatic protein synthesis. We did not observe

increases in pancreatic amylase gene expression, and lipase mRNA transcripts were significantly

lower after Ex4 administration. Furthermore, studies of pancreatic enzyme levels in rodents

have been inconsistent, demonstrating either no change or small increases in amylase following

administration of GLP1R agonists (17; 3335). Our current studies demonstrate that serum

lipase levels were lower, whereas amylase levels and pancreatic content of amylase and lipase

proteins (Supplementary Table 2) remained similar after treatment with Ex4. Hence, non

diabetic mice do not reveal a putative mechanism linking GLP1R signaling to the expression or

activity of amylase and lipase.

Although, most proteins in the pancreas were proportionately increased to a similar

extent by Ex4 treatment, some proteins, including Reg3, Reg2 and Reg1, were preferentially

increased by Ex4. The Reg proteins are small secreted proteins belonging to the calcium

dependent lectin (Ctype lectin) superfamily, encoded by 4 genes (Reg1, 2, 3 and 4). Reg1 is

predominantly localized to acinar cells, however it may be upregulated in islets under

pathological conditions including pancreatic resection or diabetes (36). Although it is unclear

how Ex4 induces Reg gene and protein expression, Reg expression is induced by

proinflammatory cytokines, growth factors, and experimental pancreatic injury (36). Some

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investigators have inferred that induction of pancreatic Reg3 expression reflects the presence of

mild subclinical pancreatitis (37), however Reg proteins, including Reg3 also exert anti

inflammatory actions (38) and reduction of Reg expression significantly worsened the severity of

experimental pancreatitis in rats (39). Furthermore, our unbiased analysis of the entire pancreatic proteome did not reveal a protein profile suggestive of a proinflammatory state following Ex4

administration (Supplementary Table 1). Hence, the biological significance of the robust GLP

1Rdependent induction of Reg gene and protein expression in the exocrine pancreas requires

further investigation.

In summary, activation of the GLP1R rapidly increases pancreatic gene and protein expression

and pancreatic weight in mice. The cellular site(s) of GLP1R expression important for

transduction of these signals to the exocrine pancreas remain unclear, however the available

evidence suggests that these effects are indirect, and not mediated through acinar Glp1r expression (6). Our data open a new area of research into understanding how GLP1R signaling communicates with the exocrine pancreas, and explain previous observations of increased pancreas weight following pharmacological administration of GLP1R agonists in preclinical studies.

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Author contributions

JK, LB, XC, TA, JC, TS, JJ, BL carried out experiments, analyzed data, wrote and reviewed the manuscript. DJD designed experiments, reviewed data and wrote the manuscript.

Acknowledgments

DJD is the main guarantor of this work and takes responsibility for all content. DJD is supported in part by the Canada Research Chairs Program and a Banting and Best Diabetes CentreNovo Nordisk Chair in Incretin Biology. JC was supported by a CIHR Postdoctoral fellowship. These studies were funded in part by operating grant support from i) the Canadian Institutes of Health Research 123391 and ii) Novo Nordisk Inc.

Conflict of Interest: DJD has been a consultant to Novo Nordisk Inc and other companies that develop and/or sell incretinbased therapies including Arisaph Pharmaceuticals Inc., Intarcia Therapeutics, Merck Research Laboratories, MedImmune, Receptos, Sanofi, Takeda, and Transition Pharmaceuticals Inc. Neither Dr. Drucker nor his family members hold stock directly or indirectly in any of these companies. TS and JJ are employees of Gubra Inc.

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1. Campbell JE, Drucker DJ. Pharmacology physiology and mechanisms of incretin hormone action. Cell metabolism 2013;17:819-837 2. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696-1705 3. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs--FDA and EMA assessment. The New England journal of medicine 2014;370:794-797 4. Drucker DJ. Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls. Diabetes 2013;62:3316-3323 5. Nauck MA. A critical analysis of the clinical use of incretin-based therapies: The benefits by far outweigh the potential risks. Diabetes care 2013;36:2126-2132 6. Richards P, Parker HE, Adriaenssens AE, et al. Identification and characterisation of glucagon-like peptide-1 receptor expressing cells using a new transgenic mouse model. Diabetes 2014;63:1224-1233 7. Baggio LL, Huang Q, Cao X, Drucker DJ. The long-acting albumin-exendin-4 GLP-1R agonist CJC-1134 engages central and peripheral mechanisms regulating glucose homeostasis. Gastroenterology 2008;134:1137-1147 8. Koehler JA, Baggio LL, Lamont BJ, Ali S, Drucker DJ. GLP-1 receptor activation modulates pancreatitis- associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice. Diabetes 2009;58:2148-2161 9. Gotfredsen CF, Molck AM, Thorup I, et al. The human GLP-1 analogs liraglutide and semaglutide: Absence of histopathological effects on the pancreas in nonhuman primates. Diabetes 2014;63:2486- 2497 10. Parkes DG, Mace KF, Trautmann ME. Discovery and development of exenatide: the first antidiabetic agent to leverage the multiple benefits of the incretin hormone, GLP-1. Expert opinion on drug discovery 2013;8:219-244 11. Hansotia T, Baggio LL, Delmeire D, et al. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes 2004;53:1326-1335 12. Scrocchi LA, Brown TJ, MacLusky N, et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide receptor gene. Nature medicine 1996;2:1254-1258 13. Dalboge LS, Almholt DL, Neerup TS, et al. Characterisation of age-dependent beta cell dynamics in the male db/db mice. PloS one 2013;8:e82813 14. Lamont BJ, Li Y, Kwan E, Brown TJ, Gaisano H, Drucker DJ. Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice. The Journal of clinical investigation 2012;122:388-402 15. Wisniewski JR, Zougman A, Nagaraj N, Mann M. Universal sample preparation method for proteome analysis. Nature methods 2009;6:359-362 16. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. The Lancet 2008;372:1240-1250 17. Tatarkiewicz K, Sablan EJ, Polizzi CJ, Villescaz C, Parkes DG. Long-term metabolic benefits of exenatide in mice are mediated solely via the known glucagon-like peptide 1 receptor. American journal of physiology Regulatory, integrative and comparative physiology 2014;306:R490-498 18. Beglinger S, Drewe J, Schirra J, Goke B, D'Amato M, Beglinger C. Role of fat hydrolysis in regulating glucagon-like Peptide-1 secretion. The Journal of clinical endocrinology and metabolism 2010;95:879- 886 19. Bragado MJ, Tashiro M, Williams JA. Regulation of the initiation of pancreatic digestive enzyme protein synthesis by cholecystokinin in rat pancreas in vivo. Gastroenterology 2000;119:1731-1739

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20. Crozier SJ, Sans MD, Wang JY, Lentz SI, Ernst SA, Williams JA. CCK-independent mTORC1 activation during dietary protein-induced exocrine pancreas growth. American Journal of Physiology - Gastrointestinal and Liver Physiology 2010;299:G1154-G1163 21. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012;149:274-293 22. Simonsen L, Pilgaard S, Orskov C, et al. Exendin-4, but not dipeptidyl peptidase IV inhibition, increases small intestinal mass in GK rats. American journal of physiology Gastrointestinal and liver physiology 2007;293:G288-295 23. Sturis J, Gotfredsen CF, Romer J, et al. GLP-1 derivative liraglutide in rats with beta-cell deficiencies: influence of metabolic state on beta-cell mass dynamics. Br J Pharmacol 2003;140:123-132 24. Lamont BJ, Drucker DJ. Differential anti-diabetic efficacy of incretin agonists vs. DPP-4 inhibition in high fat fed mice. Diabetes 2008;57:190-198 25. Ellenbroek JH, Tons HA, Westerouen van Meeteren MJ, et al. Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice. Diabetologia 2013;56:1980-1986 26. Koehler JA, Drucker DJ. Activation of GLP-1 receptor signaling does not modify the growth or apoptosis of human pancreatic cancer cells. Diabetes 2006;55:1369-1379 27. Zhao H, Wei R, Wang L, et al. Activation of glucagon-like peptide-1 receptor inhibits growth and promotes apoptosis of human pancreatic cancer cells in a cAMP-dependent manner. American journal of physiology Endocrinology and metabolism 2014; 28. Barreto SG, Carati CJ, Toouli J, Saccone GT. The islet-acinar axis of the pancreas: more than just insulin. American journal of physiology Gastrointestinal and liver physiology 2010;299:G10-22 29. Rinaman L. Interoceptive stress activates glucagon-like peptide-1 neurons that project to the hypothalamus. Am J Physiol 1999;277:R582-590 30. Hisadome K, Reimann F, Gribble FM, Trapp S. CCK stimulation of GLP-1 neurons involves alpha1- adrenoceptor-mediated increase in glutamatergic synaptic inputs. Diabetes 2011;60:2701-2709 31. Habib AM, Richards P, Cairns LS, et al. Overlap of Endocrine Hormone Expression in the Mouse Intestine Revealed by Transcriptional Profiling and Flow Cytometry. Endocrinology 2012;153:3054-3065 32. Williams JA. Regulation of acinar cell function in the pancreas. Current opinion in gastroenterology 2010;26:478-483 33. Tatarkiewicz K, Smith PA, Sablan EJ, et al. Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents. American journal of physiology Endocrinology and metabolism 2010;299:E1076-1086 34. Vrang N, Jelsing J, Simonsen L, et al. The effects of 13 wk of liraglutide treatment on endocrine and exocrine pancreas in male and female ZDF rats: a quantitative and qualitative analysis revealing no evidence of drug-induced pancreatitis. American journal of physiology Endocrinology and metabolism 2012;303:E253-264 35. Tatarkiewicz K, Belanger P, Gu G, Parkes D, Roy D. No evidence of drug-induced pancreatitis in rats treated with exenatide for 13 weeks. Diabetes Obes Metab 2013;15:417-426 36. Parikh A, Stephan AF, Tzanakakis ES. Regenerating proteins and their expression, regulation and signaling. Biomolecular concepts 2012;3:57-70 37. Mondragon A, Davidsson D, Kyriakoudi S, et al. Divergent effects of liraglutide, exendin-4, and sitagliptin on Beta-cell mass and indicators of pancreatitis in a mouse model of hyperglycaemia. PloS one 2014;9:e104873 38. Loonen LM, Stolte EH, Jaklofsky MT, et al. REG3gamma-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum. Mucosal immunology 2014;7:939-947 39. Zhang H, Kandil E, Lin YY, Levi G, Zenilman ME. Targeted inhibition of gene expression of pancreatitis-associated proteins exacerbates the severity of acute pancreatitis in rats. Scandinavian journal of gastroenterology 2004;39:870-881

Diabetes Page 22 of 73

Page 23 of 73 Diabetes

Figure Legends:

Figure 1: GLP-1R agonists increase pancreas weight. A-C) C57BL/6 mice were administered exogenous Ex4 (10 nmol/kg, BID) or vehicle (PBS) for 7 days (A) or 4 weeks (B). Pancreas weight is shown as absolute weight (left panels) or as a % of the final body weight (right panels). C) Pancreas weight in Ex4 treated mice is shown as a fold increase relative to pancreas weight in PBStreated mice treated after 7 days (left panel) or 4 weeks (right panel) of treatment. n=9 (7 days) or n=10 (4 weeks) in each group. Data are means ± SE. ** p<0.01, *** p<0.001 Ex4 vs PBS. D) Water content (edema), DNA and protein content in the pancreas of mice treated with Ex4 or PBS for 4 weeks. Edema was calculated following desiccation and is expressed as a percentage of wet weight (wet weightdry weight/wet weight x100). DNA and protein content are expressed per mg of pancreatic tissue n=10 in each group. Data are means ± SE. ** p<0.01 *** p<0.001 Ex4 vs PBS. E) Quantification of Ki67+ cells in the exocrine pancreas of C57BL/6 mice treated with Ex4 or PBS for 496h. Shown is the Ki67+ area as a percentage of the total exocrine area analyzed. F-G) Stereological quantification of pancreatic exocrine mass of F) C57BL/6 mice administered exogenous Ex4, liraglutide (Lira), or PBS for 14 days. n=10 in each group, or G) Glp1r+/+ and Glp1r-/- littermate controls administered exogenous Ex4, or PBS for 14 days. n=1012 in each group. The total pancreas mass and total exocrine pancreas mass were quantified using manual pointcounting using newCAST software (Visiopharm). Corrected pancreas mass excludes nonpancreatic tissue elements e.g. lymph and fat. The exocrine mass was determined as the corrected pancreas mass with the endocrine mass excluded. The total mass of ductal epithelial cells was quantified by manual pointcounting of ck19labeled duct cells. Quantification of beta and nonbeta cell masses was done by automatic image analysis of immunohistochemicallylabeled sections using Visiomorph software (Visiopharm). Shown is the corrected pancreas mass (pancreas mass excluding nonpancreatic tissue elements eg lymph and fat) and exocrine mass (corrected pancreas massendocrine mass). Data are means ± SE. ** p<0.01, p*** p<0.001 vs control.

Figure 2: A-B) Cckbr-/-, Cckar-/-, Cckar-/-:Cckbr-/- (DKO) and WT littermate control mice were administered exogenous Ex4 or vehicle (PBS) for 10 days. Pancreas weight is shown (A) as a % of the final body weight (BW), or (B) as a foldincrease relative to PBStreated mice (normalized to BW). Results are expressed as means ± SE. ** p<0.01, p*** p<0.001 Ex4 vs PBS. n = 610 female mice in each group. C) Pancreas weight shown as a % of final body weight in Glp1r+/+ and Glp1r-/- mice maintained on control diet (CD) or high protein diet (HPD) for 7 days. Results are expressed as means ± SE. *P < 0.05, p*** p<0.001 HPD vs CD. n = 46 in each group.

Figure 3A-B) Western blot analysis of whole cell lysates of pancreas tissue from C57BL/6 mice administered exogenous Ex4 or vehicle (PBS) for 4 or 12h (A), or 2 to 7 days (B) as indicated. Each lane represents pancreatic protein from an individual mouse. C) Quantification of levels of

Diabetes Page 24 of 73

phosphorylated S6 and the abundance of the hyperphosphorylated form of 4EBP1 (4EBP1γ form of 4EBP1 AB). *P < 0.05, *** p<0.001 Ex4 vs PBS. D) Western blot analysis of whole cell pancreas lysates from Glp1r+/+ and Glp1r-/- mice administered Ex4 or PBS for 3 days. Each lane represents an individual mouse. EF) Pancreas weight (E), and small bowel weight (F) as a percentage of body weight of male C57BL/6 mice administered vehicle or rapamycin (Rap, 2 mg/kg 1x daily, ip) together with Ex4 or PBS for 7 days. * p<0.05,** p<0.01, p*** p<0.001 vs control. G) Western blot analysis of pancreatic lysates from WT mice administered vehicle or rapamycin 30 min prior to Ex4 or PBS for 3 days. Each lane represents an individual mouse. H) qPCR analysis of RNA isolated from the pancreas of the above treated mice. The levels of the indicated transcripts were determined by realtime PCR, normalized to cyclophillin (Ppia) mRNA content. Results are expressed as means ± SE. *P < 0.05, ** p<0.01, *** p<0.001 Ex4 vs PBS, #P < 0.05 rapamycin vs vehicle. n=5 in each group. R, rapamycin; P, PBS; E, Ex4.

Figure 4: A-C,E) qPCR analysis of RNA isolated from the pancreas of mice treated with AB) Ex4 or PBS for 4h to 7 days, C) Ex4 or PBS for 4 weeks, or E) Ex4 or PBS for 7 days, with or without coadministration of rapamycin. The levels of the indicated transcripts were determined by realtime PCR, normalized to cyclophilin (Ppia) mRNA content. Results are expressed as a fold difference relative to PBS and expressed as means ± SE. *P < 0.05, ** p<0.01, p*** p<0.001 Ex4 vs PBS n = 5 male C57BL/6 mice (A-B), n = 12 male and female mice (C), or n = 5 male C57BL/6 mice in each group (E). D) Enzymatic lipase and amylase levels in serum from C57BL/6 mice administered Ex4 or PBS for 1 month (n=10 in each group) or administered 5 sequential hourly ip injections of caerulein, 50 g/kg body wt (n=2) as described in methods. Results are expressed as means ± SE. ** p<0.01 Ex4 vs PBS.

Table 1: Summary of proteomic analysis in whole pancreas tissue of male C57BL/6 mice administered Ex4 or vehicle (PBS) for 7 days. Shown are proteins with fold changes >2 and False Discovery Rates (FDR) ≤0.05 from spectral count analysis of whole pancreas following Ex4 administration. FDR is the error rate estimated for a particular Zstatistic threshold calculated from the replicate data consistency and degree of change between control (PBS) and experimental (Ex4) sample. Scale of 01 with 1 being random. Zstatistic (Log Fold Change divided by the standard error of Log Fold Change) measures the statistical significance of the change.

Page 25 of 73 Diabetes

Table 1: Summary of proteomic analysis in whole pancreas tissue of male C57BL/6 mice administered Ex4 or vehicle for 7 days.

Gene Gene Protein Name Function Fold

ID Name Change

19693 Reg2 Pancreatic thread/ expressed in regenerating islets and normal 1224.62

stone protein 2 exocrine pancreas

stimulates growth of beta cells

18489 Reg3b Regenerating islet antiinflammatory 325.09

derived 3 beta secreted protein that contain a Ctype lectin

domain involved in carbohydrate binding

18984 Por P450 (Cytochrome) required for electron transport from NADP 155.60

Oxidoreductase to cytochrome P450 in the ER and

mitochondrial memb (eg lipid oxidation)

16592 Fabp5 Fatty acid binding play roles in fatty acid uptake, transport, and 51.05

protein 5 metabolism

63913 Fam129a Family With Sequence regulates phosphorylation of proteins 49.20

Similarity 129, involved in translation

Member A (eiF2a, EIF4EBP1,RPS6KB1)

may be involved in ER stress response

74915 Atp6v1e2 V1Type Proton enzyme transporter that functions to acidify 12.65

Diabetes Page 26 of 73

ATPase Subunit E 2 intracellular compartments in eukaryotic cells

important role in receptormediated

endocytosis, protein degradation and coupled

transport

436523 Gm5771 trypsinogen 12 trypsin 12 precursor (zymogen) 11.27

22073 Prss3 trypsinogen 3 mesotrypsin precursor (zymogen) 10.67

103964 Try5 trypsin 5 trypsinlike serine protease 8.77

11720 Mat1a Methionine adenosyl catalyzes the transfer of the adenosyl moiety 6.55

transferase I, alpha of ATP to methionine to form S adenosyl

methionine (source of methyl groups for most

biological methylations)

17880 Myh11 Smooth muscle myosin functions as a major contractile protein 6.25

heavy chain 11

436522 Try10 trypsinigen 10 trypsin 10 precursor (zymogen) 4.42

19692 Reg1 Regenerating Islet associated with islet cell regeneration 3.95

Derived 1 /pancreatic stimulates growth of beta cells

stone protein 1 (PSP1) might act as an inhibitor of spontaneous

calcium carbonate precipitation

Page 27 of 73 Diabetes

13681 Eif4a1 Eukaryotic translation subunit of the eIF4F complex involved in cap 2.90

initiation factor 4A1 recognition and is required for mRNA binding

to ribosomes

12945 Dmbt1 Deleted in malignant involved in remodeling during exocytosis 2.84

brain tumors 1 interacts with pancreatic zymogens

involved in secretion of acinar cells

66473 Ctrb1 chymotrypsinogen B1 inactive serine protease precursor (zymogen) 2.32

22375 Wars tryptophanyltRNA "attach" tryptophan to its tRNA 2.32

synthestase induced by interferon

16612 Klk1 Glandular kallikrein 1 cleave MetLys and ArgSer bonds in 2.31

kininogen to release the vasoactive peptide,

Lysbradykinin from kininogen

319188 Hist1h2bp Histone cluster 1, H2bp a member of the histone H2B family 2.24

230721 Pabpc4 Poly(A) binding may be necessary for regulation of stability of 2.39

protein, cytoplasmic 4 labile mRNA species in in activated T cells

inducible poly(A) isolated as an activationinduced Tcell binding protein mRNA encoding protein

14118 Fbn1 Fibrillin 1 structural components of 1012 nm extra 4.45

Diabetes Page 28 of 73

cellular calciumbinding microfibrils

209027 Pycr1 Pyrroline5 enzyme that catalyzes the last step in proline 17.5

carboxylate reductase 1 biosynthesis

22074 Try4 trypsin 4 trypsin 4 precursor 1023.29

PageFigure 29 of 1:73 Diabetes A) Pancreas mass B) Pancreas mass C) Pancreas mass

0.3 ** 1.4 0.3 ** 1.4 1.4 1.4 *** *** *** 1.2 *** 1.2 1.2 1.2 0.2 0.2

1.0 g g 1.0 1.0 1.0

0.1 0.8 0.1 fold increase fold

0.8 increase fold 0.8 0.8 % of body weight body of %

0.6 weight body of % (normalized to BW) to (normalized 0.0 0.0 0.6 BW) to (normalized 0.6 0.6 PBS Ex-4 PBS Ex-4 PBS Ex-4 PBS Ex-4 PBS Ex-4 PBS Ex-4

D) Edema DNA content Protein content protein:DNA content E) # Ki67+ cells/exocrine area

) 2 80 6 300 ** 100 *** 30 PBS 75 5 80 Ex-4 4 200 20 70 ** 60 3 65 40

2 100 10

g/mg tissue g/mg tissue g/mg  60  20

% water content water % 1 (wet-dry/wet*100) 55 0 0 content protein/DNA 0 0 PBS Ex-4 PBS Ex-4 PBS Ex-4 PBS Ex-4 (mm cells/area #Ki67+ 4 h 12 h 24 h 4 d Time F) G) Pancreas mass Exocrine mass Pancreas mass Exocrine mass 400 400 400 PBS 400 PBS *** *** *** *** Ex-4 ** Ex-4 **

300 300 300 300

mg mg mg mg 200 200 200 200

100 100 100 100

0 0 0 0 PBS Ex-4 Lira PBS Ex-4 Lira Glp1r+/+ Glp1r-/- Glp1r+/+ Glp1r-/- Figure 2: Diabetes Page 30 of 73

A) Panc weight (%BW) Panc weight (%BW) Panc weight (%BW) 1.4 PBS 1.4 PBS 1.4 PBS Ex-4 Ex-4 *** Ex-4 *** *** ** 1.2 1.2 ** 1.2 **

1.0 1.0 1.0

0.8 0.8 0.8

% body weight body % weight body % weight body % 0.6 0.6 0.6 WT Cckbr-/- WT Cckar-/- WT DKO

B) Panc weight Panc weight Panc weight (fold increase) (fold increase) (fold increase) 1.4 PBS 1.4 PBS 1.4 PBS Ex-4 Ex-4 Ex-4 *** *** ** ** 1.2 *** 1.2 ** 1.2

1.0 1.0 1.0

fold increase fold increase fold

fold increase fold 0.8 0.8 0.8

(normalized to BW) to (normalized BW) to (normalized (normalized to BW) to (normalized 0.6 0.6 0.6 WT Cckbr-/- WT Cckar-/- WT DKO

C) Pancreas weight 1.4 CD HPD *** 1.2 *

1.0

0.8 % body weight body % 0.6 Glp1r+/+ Glp1r-/- PageFigure 31 of 3:73 Diabetes

A) 4 h 12 h

PBS Ex-4 PBS Ex-4 P p70 S6K P eIF2a P S6 g 4EBP1 b a

2 days 4 days 7 days B) PBS Ex-4 PBS Ex-4 PBS Ex-4

P p70 S6K P eIF2a P S6 g 4EBP1 b a

C) p-S6 4EBP1g D) Glp1r +/+ Glp1r -/- 10 PBS 2.0 PBS * * 8 Ex-4 Ex-4 PBS Ex-4 PBS Ex-4 1.5 6 * P S6 4 *** 1.0 Hsp90

2 *

relative intensity relative relative intensity relative * 0.5 0 4 h 12 h 48 h 4 d 7 d 4 h 12 h 48 h 4 d 7 d Time Time

E) Pancreas weight F) SB weight G) Rapamycin 1.2 4.5 vehicle ** 4.0 *** PBS Ex-4 PBS Ex-4 1.0 * 3.5 P S6 3.0 0.8

2.5 Hsp90

% of body weight body of % weight body of % 0.6 2.0 PBS Ex-4 R+P R+E PBS Ex-4 R+P R+E

H) Reg 3b Reg 3a p21cip slc 3a1

25 40 # 5 2.0 *** *** * 20 4 1.5 30 * 15 * 3 20 1.0 10 ** 2

5 10 1 0.5

(fold difference) (fold difference) (fold (fold difference) (fold

(fold difference) (fold * *

relative mRNA levels mRNA relative levels mRNA relative relative mRNA levels mRNA relative relative mRNA levels mRNA relative 0 0 0 0.0 PBS Ex-4 R+P R+E PBS Ex-4 R+P R+E PBS Ex-4 R+P R+E PBS Ex-4 R+P R+E Figure 4: Diabetes Page 32 of 73

A) lipase amylase

1.5 PBS 2.0 PBS Ex-4 Ex-4 1.5 1.0 ** 1.0 ** 0.5 **

0.5

(fold difference) (fold difference) (fold relative mRNA levels mRNA relative 0.0 levels mRNA relative 0.0 4 h 12 h 24 h 48 h 4 d 7 d 4 h 12 h 24 h 48 h 4 d 7 d Time Time

B) Reg 3b (PAP) socs3 350 12 PBS PBS Ex-4 300 *** Ex-4 10 *** 250 *** 200 8 *** *** *** 150 ** 6 100 4

10 * (fold difference) (fold (fold difference) (fold 2

5 relative mRNA levels mRNA relative 0 levels mRNA relative 0 4 h 12 h 24 h 48 h 4 d 7 d 4h 12h 24h 48h 4 d 7 d Time Time C) lipase amylase Reg 3b colipase

1.2 1.5 100 ** 1.2 80 0.8 1.0 0.8 ** 60 40 0.4 0.5 0.4

(fold difference) (fold

(fold difference) (fold difference) (fold

(fold difference) (fold

relative mRNA levels mRNA relative

relative mRNA levels mRNA relative levels mRNA relative relative mRNA levels mRNA relative 0.0 0.0 0 0.0 PBS Ex-4 PBS Ex-4 PBS Ex-4 PBS Ex-4

D) serum lipase serum amylase E) lipase amylase 800 40000 1.5 1.5 700 35000 600 30000 500 25000 1.0 1.0 * 80 6000 ** 60 *** ** 4000 0.5 0.5

lipase (U/L) lipase 40

amylase (U/L) amylase (fold difference) (fold

20 2000 difference) (fold relative mRNA levels mRNA relative 0 0 levels mRNA relative 0.0 0.0 PBS Ex-4 Caerulein PBS Ex-4 Caerulein PBS Ex-4 R+P R+E PBS Ex-4 R+P R+E PageSupplementary 33 of 73 Figure 1: Diabetes

A) Body weight B) Body weight C) Pancreas weight Lung weight Body weight 26 1.4 0.8 26 26 1.2 ** 0.6

22 22 22

g g g 1.0 0.4 18 18 18

0.8 0.2

% of body weight body of % weight body of % 14 14 0.6 0.0 14 PBS Ex-4 PBS Ex-4 PBS Ex-4 PBS Ex-4 PBS Ex-4

D) Endocrine mass Beta cell mass E) Endocrine mass Beta cell mass 2.0 1.5 2.5 PBS 2.0 PBS Ex-4 Ex-4 1.5 2.0 1.5 1.0

1.5

mg mg mg mg 1.0 1.0 1.0 0.5 0.5 0.5 0.5 0.0 0.0 0.0 0.0 PBS Ex-4 Lira PBS Ex-4 Lira Glp1r+/+ Glp1r-/- Glp1r+/+ Glp1r-/-

Ductal epithelial mass Non-beta cell mass Ductal epithelial mass Non-beta cell mass 1.0 0.4 PBS 0.5 PBS 3 Ex-4 Ex-4 0.8 0.3 0.4

0.6 2 0.3 mg mg 0.2 0.4 0.2 1

0.2 0.1 0.1 Cytokeratin mass (mg) mass Cytokeratin Cytokeratin mass (mg) mass Cytokeratin 0.0 0.0 0 0.0 PBS Ex-4 Lira PBS Ex-4 Lira Glp1r+/+ Glp1r-/- Glp1r+/+ Glp1r-/- Supplementary Figure 2: Diabetes Page 34 of 73

A) B) Body weights 30 PBS 0 4h 12h 24 h 2 d 4 d 7 d Ex-4/PBS Ex-4 25

g 20

10 4 h 12 h 24 h 2 d 4 d 7 d Time C) absolute panc weight panc weight %BW 0.30 PBS 1.2 PBS Ex-4 0.0568 1.1 Ex-4 *** 0.25 1.0

g 0.20 0.9 0.8 0.15

0.7 % of body weight body of % 0.10 0.6 4 h 12 h 24 h 2 d 4 d 7 d 4 h 12 h 24 h 2 d 4 d 7 d Time Time

D) DNA content Protein content Protein:DNA content

5 PBS 250 PBS 80 PBS ** Ex-4 Ex-4 Ex-4 * 4 200 60 3 150 * 40

2 100

g/mg tissue g/mg tissue g/mg   1 50 20

0 0 content protein/DNA 0 24 h 2 d 4 d 7 d 24 h 2 d 4 d 7 d 24 h 2 d 4 d 7 d Time Time Time

E) c-myc p21cip F) myc p21cip

2.0 PBS 3 PBS 1.5 1.5 Ex-4 Ex-4 1.5 2 1.0 1.0 1.0 *** 1 0.5 0.5

0.5 ** * (fold difference) (fold (fold difference) (fold ***

relative mRNA levels mRNA relative levels mRNA relative

fold difference (PPia) difference fold (PPia) difference fold relative mRNA levels mRNA relative 0.0 0 levels mRNA relative 0.0 0.0 4h 12h 24h 48h 4 d 7 d 4 h 12 h 24 h 48 h 4 d 7 d PBS Ex-4 PBS Ex-4 Time Time (h)

cyclin D1 cyclin D2 cyclin D1 cyclin D2 PBS 2.5 PBS 2.0 Ex-4 1.2 1.2 Ex-4 ns 2.0 1.5 0.8 0.8 1.5 *** 1.0 1.0 ** 0.4 0.4

0.5 0.5 ***

(fold difference) (fold

relative mRNA levels mRNA relative levels mRNA relative

relative mRNA levels mRNA relative

fold difference (PPia) difference fold (PPia) difference fold 0.0 0.0 levels mRNA relative 0.0 0.0 4h 12h 24h 48h 4 d 7 d 4h 12h 24h 48h 4 d 7 d PBS Ex-4 PBS Ex-4 Time Time PageSupplementary 35 of 73 Figure3: Diabetes A) Body weights 30 PBS Ex-4 28 Rap + PBS Rap + Ex-4

26 BW (g) BW 24

22 0 2 4 6 8 Time (days)

B) slc 7a1 glut2 pdk4

0.20 0.008 ## 0.04 # ns 0.15 0.006 0.03 ns

0.10 0.004 0.02

0.05 0.002 0.01

0.00 0.000 0.00

PBS Ex-4 R+P R+E PBS Ex-4 R+P R+E PBS Ex-4 R+P R+E

relative mRNA levels (PPia) levels mRNA relative (PPia) levels mRNA relative (PPia) levels mRNA relative

mist1 Cckar Cckbr 0.4 2.0 0.008

0.3 1.5 0.006

0.2 1.0 0.004

0.1 0.5 0.002

0.0 0.0 0.000

PBS Ex-4 R+P R+E PBS Ex-4 R+P R+E PBS Ex-4 R+P R+E

relative mRNA levels (PPia) levels mRNA relative

relative mRNA levels (PPia) levels mRNA relative (PPia) levels mRNA relative Supplementary Figure 4: Diabetes Page 36 of 73

A) Reg 2 por fabp5 fam129a 250 1.5 2.0 2.0 *** 200 1.5 1.5 1.0 150 1.0 1.0 100 0.5

50 0.5 0.5

(fold difference) (fold difference) (fold

(fold difference) (fold

relative mRNA levels mRNA relative levels mRNA relative relative mRNA levels mRNA relative relative mRNA levels mRNA relative 0 0.0 0.0 0.0 PBS Ex-4 PBS Ex-4 PBS Ex-4 PBS Ex-4

Reg 1 dmbt1 wars eif4a1 4 2.0 2.0 2.0 * *** 3 1.5 1.5 1.5

2 1.0 1.0 1.0

1 0.5 0.5 0.5

(fold difference) (fold

relative mRNA levels mRNA relative

relative mRNA levels mRNA relative relative mRNA levels mRNA relative 0 0.0 levels mRNA relative 0.0 0.0 PBS Ex-4 PBS Ex-4 PBS Ex-4 PBS Ex-4

B) Reg 2 por fabp5 fam129a 40 1.5 1.5 1.5 *** 30 1.0 1.0 1.0 20 0.5 0.5 0.5

(fold difference) (fold difference) (fold difference) (fold difference) (fold

relative mRNA levels mRNA relative levels mRNA relative levels mRNA relative 0 0.0 levels mRNA relative 0.0 0.0 PBS Ex-4 PBS Ex-4 PBS Ex-4 PBS Ex-4

Reg 1 dmbt1 wars 1.5 1.5 1.5

1.0 1.0 1.0

0.5 0.5 0.5

(fold difference) (fold difference) (fold difference) (fold

relative mRNA levels mRNA relative levels mRNA relative 0.0 levels mRNA relative 0.0 0.0 PBS Ex-4 PBS Ex-4 PBS Ex-4

C) whole panc whole panc whole panc 1.05 islets 1.2 islets 50 islets 1.00 1.0 40 0.8 0.008 30 0.006 0.6 20 0.004 0.4

0.002 0.2 10

relative mRNA levels mRNA relative relative mRNA levels mRNA relative relative mRNA levels mRNA relative 0.000 0.0 0 amylase lipase colipase reg2 reg3b reg1 dmbt1 por fabp5 fam129a eif4a1 wars gcg glp1r ins2 PageSupplementary 37 of 73 Figure 5: Diabetes

A) Reg3

PBS

Ex-4

B) P-S6

i Diabetes Page 38 of 73

Supplementary Figure 1: A-B) Final body weights of C57BL/6 mice administered exogenous Ex-4 (10 nmol/kg, BID) or vehicle (PBS) for 7 days (A) or 4 weeks (B). n=9 (7 days) or n=10 (4 weeks) in each group. Data are means ± SE. C) Pancreas and lung weights (as a percentage of body weight) and final body weights of C57BL/6 mice treated with Ex-4 for 7 days. n=4 in each group. Data are means ± SE. ** p<0.01 Ex-4 vs PBS. D-E) Stereological quantification of pancreatic mass of D) C57BL/6 mice administered exogenous Ex-4, liraglutide, or vehicle (PBS) for 14 days. n=10 in each group, or E) Glp1r+/+ and Glp1r-/- littermate controls administered exogenous Ex-4, or vehicle (PBS) for 14 days. n=10-12 in each group. Shown is the endocrine mass (mass of beta and non-beta cells inside the islets), beta cell mass (insulin immunoreactivity), ductal epithelial mass (cytokeratin 19 immunoreactivity), and non-beta cell mass (glucagon, somatostatin and pancreatic polypeptide immunoreactivity). Data are means ± SE.

Supplementary Figure 2: Ex-4 increases pancreas weight and protein content, but not DNA content following 7 days of treatment. Schematic representation of the experiment is shown in (A) and body weight in (B). C) Absolute pancreas weight (left panel) or pancreas weight (as a percentage of body weight, right panel)) of C57BL/6 mice treated with Ex-4 or PBS for 4h-7 days. n=5 in each group. *** p<0.001 Ex-4 vs PBS. D) DNA content (left panel), protein content (middle panel) and DNA:protein ratio (right panel) per mg of pancreas tissue for mice treated with Ex-4 or PBS for 24h-7 days. *P < 0.05, ** p<0.01 Ex-4 vs PBS. (E-F) qPCR analysis of RNA from pancreata of mice treated for 4h-7 days (E) or 4 weeks (F). The levels of the indicated transcripts were determined by real-time PCR, normalized to cyclophilin (Ppia) mRNA content. Results are expressed as a fold difference relative to PBS and as means ± SE. *P < 0.05, ** p<0.01, p*** p<0.001 Ex-4 vs PBS n = 5 (E) or 10 (F) mice in each group.

Supplementary Figure 3: A) Body weights of mice administered Ex-4 or PBS with or without pretreatment with rapamycin (2 mg/kg 1x daily ip) over the course of the 7 day treatment as indicated. B) qPCR analysis of RNA isolated from the pancreas of the above treated mice. The levels of the indicated transcripts were determined by real-time PCR, normalized to cyclophilin (Ppia) mRNA content. Results are expressed as means ± SE. #P < 0.05, ## p<0.01 rapamycin vs vehicle. n = 5 male C57BL/6 mice in each group.

Supplementary Figure 4: A-B) qPCR analysis of pancreatic RNA from mice treated with Ex-4 or PBS for 7 days (A), or 4 weeks (B). The levels of the indicated transcripts were determined by real-time PCR, normalized to cyclophilin (Ppia) mRNA content. Results are expressed as a fold difference relative to PBS an as means ± SE. *P < 0.05, p*** p<0.001 Ex-4 vs PBS. n = 5 male C57BL/6 mice (A) or n = 12 male and female mice (B). C) qPCR analysis of RNA isolated from whole pancreas tissue or islets isolated from WT mice. The levels of the indicated transcripts were determined by real-time PCR, normalized to cyclophilin (Ppia) mRNA content. Results are Page 39 of 73 Diabetes

expressed as means ± SE relative to whole pancreas tissue. n = 1 (whole pancreas, or islets isolated from 1 mouse).

Supplementary Figure 5: Immunohistochemical localization of Reg3 (A) and phospho-S6 (B) in the pancreas of mice treated with vehicle (PBS) or Ex-4 for 1 week (A) or Ex-4 for 3 days (B). Photomicrographs are representative of results detected in pancreata from four mice per group. Islets are represented with an i. Rare Reg3-immunopositive acinar cells in control (PBS) treated mice (A) or infrequent phospho-S6-immunopositive cells in islets (B) are indicated by the arrows. Magnification 400x (left panel) or digital enlargement of the area enclosed in the square.

Supplementary Table 1: Elucidation of the pancreatic proteome in mice treated with saline vs. exendin-4. Data from the proteomic analysis (Qspec analysis) of whole pancreas tissue from male C57BL/6 mice administered Ex-4 or vehicle (PBS) for 7 days. n=5 for control (PBS) and 4 for treatment (Ex-4). Shown is the protein ID, Gene ID, Gene name, individual spectral counts for each mouse (S1-S5, control (PBS): S6-S9, Ex-4 treatment), Log Fold Change Zstatistic, and False discovery rate (FDR). Log Fold Change values (natural log of estimated fold change) indicates the increase or decrease of protein concentration after 7 days, Zstatistic (Log Fold Change divided by the standard error of Log Fold Change) measures the statistical significance of the change, and False discovery rate (FDR) is the error rate estimated for a particular Zstatistic threshold calculated from the replicate data consistency and degree of change between control (PBS) and experimental (Ex-4) for each protein. Scale of 0-1 with 1 being random. Fold differences >2 and 5% or 0.05 fdr up or 0.05 fdr down was chosen as a cutoff for the summary data (Table 1).. FDRup: Global FDR for up-regulation in treatment (Ex-4) over control (PBS) treated mice. FDRdown: GlobalFDR for down-regulation in treatment over control. 2µg of digested sample was analyzed using nano-LC/MS with an Eksigent Ultra HPLC and a home-packed 75µm C18 column (Reprosil 3um C18). Buffer A was 0.1% formic acid in water; buffer B was 0.1% formic acid in ACN. The HPLC delivered an acetonitrile gradient over 230 min (2-35% buffer B over 180 min, 35-80% buffer B over 10 min, hold buffer B at 80% 10 min, and return to 2% B at 215min). The DDA parameters for acquisition on the TripleTOF 5600 were 1 MS scan (250ms; mass range 400-1250) followed by a) up to 20 MS/MS scans (100ms each). Candidate ions between 2-5 charge state and above a minimum threshold of 200 counts per second were isolated using a window of 0.7amu. Previous candidate ions were dynamically excluded for 20sec with a 50 mDa window. Mass spectrometry data extraction: Wiff files were converted to mzXML using AB Sciex MS Data Converter and ProteoWizard (3.0.4468; (1) and analyzed using the iProphet pipeline (2) implemented within ProHits (3) as follows. The database consisted of the mouse complements of the RefSeq protein database (version 53) supplemented with “common contaminants” from the Max Planck Institute (http://maxquant.org/downloads.htm) and the Global Proteome Machine (GPM; http://www.thegpm.org/crap/index.html). The search database consisted of forward and reversed sequences (labeled “DECOY”); in total 58202 entries were searched. The search engines used Diabetes Page 40 of 73

were Mascot (2.3.02; Matrix Science) and Comet (2012.01 rev.3; (4) with trypsin specificity (1 missed cleavages were allowed) , carbamidomethyl (C) was set as a fixed modification and deamidation (NQ) and oxidation (M) as variable modifications. Charges +2, +3 and +4 were allowed, and the parent mass tolerance was set at 30 ppm while the fragment bin tolerance was set at 0.15 amu. The resulting Comet and Mascot search results were individually processed by PeptideProphet (5) and combined into a final iProphet output using the Trans-Proteomic Pipeline (Linux version, v0.0 Development trunk rev 0, Build 201303061711). TPP options were as follows: general options are -p0.05 -x20 -PPM -d"DECOY", iProphet options are –ipPRIME and PeptideProphet options are –OpdP. All proteins with a minimal iProphet probability of 0.95 were exported and processed with the QSPEC program. This corresponded to 1959 proteins at an estimated FDR of ~1%. The QSPEC program (6) was used to identify differential protein abundance between pancreas samples from Ex-4 and PBS (control) treated mice by statistical analysis of spectral count data exported from iProphet. QSPEC reports log fold change, Zstatistic and false discovery ratios (FDR) for fold change data for each protein.

Supplementary Table 2: Summary of proteomics data for amylase and lipase –related proteins, and islet-associated proteins. Log fold change represents the overall change in pancreas protein after 7 days of treatment. Zstatistic reports a combined value of the confidence and fold change data. Individual fdr values for fold changes as reported by the Qspec algorithm.

References:

1. Kessner D, Chambers M, Burke R, Agus D, Mallick P. ProteoWizard: open source software for rapid proteomics tools development. Bioinformatics 2008;24:2534-2536 2. Shteynberg D, Deutsch EW, Lam H, et al. iProphet: multi-level integrative analysis of shotgun proteomic data improves peptide and protein identification rates and error estimates. Molecular & cellular proteomics : MCP 2011;10:M111 007690 3. Liu G, Zhang J, Larsen B, et al. ProHits: integrated software for mass spectrometry-based interaction proteomics. Nature biotechnology 2010;28:1015-1017 4. Eng JK, Jahan TA, Hoopmann MR. Comet: an open-source MS/MS sequence database search tool. Proteomics 2013;13:22-24 5. Keller A, Nesvizhskii AI, Kolker E, Aebersold R. Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search. Anal. Chem 2002;74:5383-5392 6. Choi H, Fermin D, Nesvizhskii AI. Significance analysis of spectral count data in label-free shotgun proteomics. Molecular & cellular proteomics : MCP 2008;7:2373-2385

Page 41 of 73 Diabetes

Supplementary Table 1: Elucidation of the pancreatic proteome in mice treated with saline vs. Ex-4.

Spectral counts Control (PBS) Treatment (Ex-4) Log Fold ProteinID Gene ID Gene Name S1 S2 S3 S4 S5 S6 S7 S8 S9 Change Zstatistic fdr FDRup FDRdown 298676467 545562 Amy2b 0 0 0 0 2 0 0 109 0 3.247 7.114 0 0 0.9920 6677705 19693 Reg2 0 0 0 0 0 18 19 25 16 3.088 5.820 0 0 0.9932 6754980 18489 Reg3b 0 0 0 0 0 14 9 12 10 2.512 5.314 0 0 0.9938 6679421 18984 Por 0 2 0 0 2 10 13 13 12 2.192 5.203 0 0 0.9941 6754450 16592 Fabp5 2 2 1 1 3 9 9 9 12 1.708 4.437 0 0 0.9952 241982745 63913 Fam129a 1 3 5 1 14 20 26 28 28 1.692 7.242 0 0 0.9917 309270584 100040929 Gm10362 0 0 0 0 10 0 0 22 22 1.394 4.724 0 0 0.9947 254911018 74915 Atp6v1e2 0 0 8 0 0 10 17 0 0 1.102 3.014 0.0021 0.0002 0.9984 20824630 233075 Gm4883 0 0 0 0 0 0 0 8 0 1.088 1.921 0.3132 0.0636 1 84781768 436523 Gm5771 0 2 0 0 4 3 2 9 6 1.052 2.777 0.0069 0.0008 0.9998 20912377 241621 Gm13981 2 0 0 1 4 5 4 5 6 1.033 2.456 0.0333 0.0049 1 6755891 22073 Prss3 0 8 1 0 7 6 6 15 13 1.028 3.460 0.0001 0.0000 0.9966 149260690 100040961 Gm10145 0 4 0 0 0 0 5 5 6 1.027 2.387 0.0508 0.0070 1 13994195 19045 Ppp1ca 0 2 0 0 0 3 3 2 4 0.987 1.900 0.3259 0.0692 1 158517895 239570 Ttc38 0 0 2 0 2 3 2 5 4 0.958 2.102 0.2100 0.0289 1 51010909 103964 Try5 0 25 0 0 48 28 40 38 48 0.943 6.740 0 0 0.9927 6755310 19695 Reg3g 0 0 0 0 0 4 1 4 0 0.917 1.739 0.4350 0.1237 1 51921315 269608 Plekhg5 0 0 0 0 0 2 2 3 2 0.884 1.418 0.7897 0.3060 1 19526790 11720 Mat1a 2 3 3 3 12 7 10 8 16 0.816 2.933 0.0033 0.0003 0.998802 241982716 17880 Myh11 1 0 2 1 11 5 2 10 11 0.796 2.557 0.0190 0.0029 1 225637487 16790 Anpep 0 0 1 0 1 2 2 1 3 0.778 1.315 0.9720 0.3891 1 33563250 13346 Des 0 1 0 0 1 2 1 2 3 0.725 1.197 1 0.5020 1 157277948 19684 Rdx 2 1 0 2 0 5 4 0 1 0.716 1.473 0.7044 0.2667 1 19882207 110196 Fdps 0 0 1 0 6 2 0 6 7 0.694 1.724 0.4467 0.1303 1 309271453 631331 Gm7061 0 1 1 1 0 0 0 2 3 0.651 1.085 1 0.6231 1 84781771 436522 Try10 10 16 5 0 27 20 19 17 33 0.645 3.871 7E-06 0 0.9957 33413404 76282 Gpt 1 0 0 1 2 0 3 2 3 0.626 1.175 1 0.5238 1 31543108 16784 Lamp2 1 2 1 2 2 3 3 3 3 0.624 1.401 0.8170 0.3189 1 240120112 14085 Fah 2 1 2 1 1 3 2 2 3 0.612 1.196 1 0.5033 1 51243034 237542 Osbpl8 0 0 0 0 1 4 0 0 0 0.611 0.972 1 0.7550 1 6677703 19692 Reg1 13 11 11 10 15 22 23 25 18 0.597 3.447 0.0001 0.0000 0.9967 30841008 19330 Rab18 2 0 0 1 2 2 3 3 2 0.592 1.169 1 0.5307 1 22122585 225027 Srsf7 1 0 0 0 0 0 2 2 2 0.587 0.932 1 0.8018 1 31560132 68371 Pbld1 0 0 1 7 3 0 0 7 9 0.572 1.499 0.6686 0.2502 1 124486895 110208 Pgd 0 3 2 2 5 0 3 7 7 0.563 1.560 0.5943 0.2122 1 198278553 98932 Myl9 2 2 2 1 0 1 0 5 4 0.562 1.148 1 0.5532 1 294832028 50799 Slc25a13 0 0 0 0 1 0 0 0 4 0.559 0.918 1 0.8189 1 7305619 22225 Usp5 0 0 0 0 1 1 2 2 2 0.555 0.945 1 0.7862 1 83745139 319448 Fndc3a 1 2 2 0 7 3 3 7 5 0.553 1.543 0.6129 0.2223 1 149248853 381346 Gm13194 0 2 2 2 3 4 3 4 3 0.553 1.357 0.8951 0.3533 1 18875380 170758 Rac3 3 4 4 0 0 3 4 4 7 0.545 1.469 0.7106 0.2694 1 254750698 18220 Nucb1 0 1 0 0 4 3 0 3 4 0.541 1.118 1 0.5848 1 33468863 17750 Mt2 0 0 0 0 0 0 2 0 3 0.533 0.841 1 0.9079 0.9987 31560656 18458 Pabpc1 0 0 1 0 9 3 2 5 7 0.524 1.441 0.7522 0.2887 1 31543918 70620 Ube2v2 4 2 2 2 0 2 4 4 4 0.493 1.192 1 0.5060 1 13385384 66997 Psmd12 0 3 1 0 4 2 3 4 4 0.491 1.175 1 0.5252 1 281427153 66111 Tmed3 2 1 2 1 2 2 2 2 4 0.488 1.010 1 0.7099 1 6681137 13167 Dbi 5 5 7 4 7 9 9 10 8 0.484 1.967 0.2864 0.0527 1 6671672 12343 Capza2 0 1 3 0 3 0 0 5 4 0.479 1.054 1 0.6577 1 39652626 23827 Bpnt1 1 1 1 1 7 3 1 4 6 0.472 1.055 1 0.6577 1 116517301 19205 Ptbp1 0 2 4 3 10 8 2 9 6 0.468 1.522 0.6382 0.2351 1 85701680 77055 Krt76 0 0 0 0 0 1 0 2 2 0.468 0.722 1 1 0.9856 21450625 13681 Eif4a1 14 25 18 12 17 22 24 28 35 0.463 3.133 0.0010 0.0001 0.9979 87239967 12945 Dmbt1 19 15 18 15 41 34 34 38 30 0.453 3.340 0.0002 0.00002 0.9971 30794164 74325 Cltb 3 5 3 2 7 4 4 7 10 0.452 1.449 0.7399 0.2831 1 56699423 17999 Nedd4 0 1 1 0 4 1 0 4 4 0.449 0.925 1 0.8111 1 Diabetes Page 42 of 73

194353962 11840 Arf1 1 5 4 2 11 4 5 8 11 0.446 1.633 0.5207 0.1720 1 359279904 59069 Tpm3 0 1 3 0 7 4 4 2 6 0.440 1.210 1 0.4886 1 149233906 100043027 Gm11575 0 1 0 0 1 1 1 2 2 0.439 0.681 1 1 0.9799 269954698 218811 Sec24c 0 0 0 0 1 1 0 3 0 0.436 0.692 1 1 0.9815 167900460 245666 Iqsec2 2 5 3 3 5 5 6 6 5 0.435 1.361 0.8878 0.3501 1 31560689 15360 Hmgcs2 0 1 0 0 0 0 0 3 0 0.435 0.674 1 1 0.9789 38198665 386649 Nsfl1c 1 0 1 0 5 1 2 3 5 0.432 0.993 1 0.7301 1 158636012 20823 Ssb 1 1 1 0 2 1 2 2 2 0.431 0.744 1 1 0.9882 21703744 209354 Eif2b1 1 1 1 1 1 1 2 0 2 0.430 0.673 1 1 0.9787 6996911 11898 Ass1 3 3 5 2 8 6 7 6 6 0.427 1.459 0.7248 0.2766 1 21704096 230908 Tardbp 2 1 1 1 2 1 1 2 4 0.427 0.803 1 0.9512 0.9949 16716569 114228 Prss1 0 0 0 0 0 0 0 2 2 0.426 0.689 1 1 0.9812 6679501 19179 Psmc1 0 0 0 0 2 0 0 3 2 0.424 0.730 1 1 0.9866 27754031 72183 Snx6 0 0 0 0 0 0 0 3 0 0.423 0.713 1 1 0.9842 27229125 71743 Coasy 0 0 0 0 1 0 0 1 3 0.421 0.689 1 1 0.9810 19527310 105675 Ppif 1 0 1 0 2 0 1 2 3 0.408 0.693 1 1 0.9815 6755308 19694 Reg3a 0 0 0 0 0 2 1 2 1 0.403 0.645 1 1 0.9746 134031994 19166 Psma2 0 1 3 0 4 1 2 4 5 0.400 0.918 1 0.8189 1 13385862 67767 Jagn1 1 0 2 1 1 0 1 3 2 0.399 0.690 1 1 0.9812 116014342 12215 Bsg 2 2 3 0 3 2 4 4 3 0.397 0.992 1 0.7300 1 29788764 11564 Adsl 0 1 0 0 2 1 0 3 2 0.395 0.676 1 1 0.9791 111607449 16627 Klra1 0 0 0 0 1 1 2 2 0 0.387 0.606 1 1 0.9682 244791271 69162 Sec31a 6 7 11 7 16 10 12 15 18 0.384 1.877 0.3401 0.0754 1 23943838 13358 Slc25a1 0 0 1 1 2 0 2 2 2 0.380 0.611 1 1 0.969095 214010170 12759 Clu 5 8 8 5 11 10 8 15 10 0.379 1.620 0.5331 0.1795 1 160333304 11806 Apoa1 5 7 3 0 12 8 7 9 9 0.377 1.521 0.6397 0.2359 1 13384850 66256 Ssr2 0 0 5 2 6 0 2 8 6 0.377 1.048 1 0.6653 1 158937300 140740 Sec63 1 2 3 0 9 2 2 5 9 0.376 1.001 1 0.7207 1 13385598 67332 Snrpd3 0 1 0 0 2 1 1 3 2 0.374 0.664 1 1 0.9774 31980969 27054 Sec23b 4 8 9 3 18 9 12 14 14 0.373 1.737 0.4365 0.1242 1 225735645 19156 Psap 5 4 7 2 6 5 7 6 9 0.369 1.337 0.9314 0.3710 1 139948802 50933 Uchl3 0 2 0 0 2 0 0 2 4 0.369 0.671 1 1 0.9785 255522937 66473 Ctrb1 131 185 102 78 222 192 188 222 229 0.365 7.410 0 0 0.9913 256818746 22375 Wars 16 16 21 10 27 24 23 32 25 0.365 2.454 0.0338 0.0049 1 31980868 16612 Klk1 19 18 20 16 21 26 25 27 29 0.364 2.607 0.0148 0.0022 1 27754103 67089 Psmc6 0 1 0 0 4 0 1 3 4 0.364 0.735 1 1 0.9871 161484654 12826 Col4a1 2 1 0 1 1 2 2 2 1 0.363 0.640 1 1 0.9738 20799907 15267 Hist2h2aa1 8 7 9 3 14 9 11 13 14 0.358 1.718 0.4514 0.1325 1 18017602 73723 Sh3bgrl3 1 1 1 1 1 2 1 2 0 0.357 0.604 1 1 0.9680 40254600 11737 Anp32a 0 5 3 0 7 4 4 5 6 0.355 0.998 1 0.7238 1 51093867 69719 Cad 1 2 0 0 3 0 1 3 4 0.355 0.748 1 1 0.9887 58331129 14738 Gpr12 1 1 1 1 2 0 0 4 0 0.351 0.606 1 1 0.9682 160420308 319188 Hist1h2bp 31 11 34 30 10 34 43 19 36 0.350 2.753 0.0076 0.0009 0.9999 7305085 14583 Gfpt1 0 0 0 0 7 0 0 3 7 0.348 0.784 1 0.9731 0.9928 257743039 16828 Ldha 9 8 9 9 17 12 13 15 18 0.346 1.856 0.3536 0.0817 1 10946870 58810 Akr1a1 2 2 2 2 10 1 3 6 10 0.346 1.092 1 0.6142 1 126521835 12461 Cct2 1 2 3 1 9 3 2 7 6 0.344 1.000 1 0.7223 1 27734136 239368 BC030476 1 1 1 1 4 1 1 4 3 0.342 0.714 1 1 0.9844 31541824 66235 Eif1ax 1 3 1 0 4 2 2 3 4 0.340 0.771 1 0.9861 0.9915 58037115 68347 0610011F06Rik 4 6 6 3 10 7 5 9 11 0.339 1.316 0.9701 0.3880 1 153791789 665155 Srp54b 8 9 14 0 19 10 11 16 19 0.331 1.634 0.5201 0.1720 1 23956096 56041 Uso1 10 10 13 3 26 9 15 21 23 0.329 1.891 0.3313 0.0717 1 6754026 14711 Gnmt 3 2 5 5 11 4 5 9 11 0.328 1.198 1 0.5006 1 239916005 50492 Thop1 0 3 2 0 16 3 3 8 11 0.327 1.095 1 0.6112 1 21313162 76308 Rab1b 2 2 3 1 3 2 2 4 4 0.323 0.829 1 0.9215 0.9975 312222784 22335 Vdac3 2 4 1 0 7 2 3 7 5 0.321 0.860 1 0.8867 1 31542095 99237 Tm9sf4 1 2 1 0 4 2 3 2 3 0.320 0.696 1 1 0.9821 165932331 109801 Glo1 1 3 3 1 4 3 3 4 3 0.315 0.809 1 0.9438 0.9956 21312994 67863 Slc25a11 1 2 2 2 4 1 3 3 5 0.315 0.685 1 1 0.9804 6753306 12425 Cckar 1 2 3 3 3 4 3 3 3 0.314 0.790 1 0.9658 0.9935 6681225 13494 Drg1 0 1 0 0 5 1 1 3 5 0.314 0.660 1 1 0.9768 Page 43 of 73 Diabetes

71037401 67366 Tmed11 7 10 7 6 12 12 10 11 13 0.309 1.484 0.6885 0.2597 1 255759941 20719 Serpinb6a 6 6 6 2 7 7 6 7 9 0.304 1.136 1 0.5660 1 21362277 52858 Cdipt 1 5 1 0 5 3 3 4 4 0.303 0.773 1 0.9847 0.9916 31981810 13177 Eci1 2 5 6 3 7 4 6 5 10 0.301 1.053 1 0.6592 1 183980004 15388 Hnrnpl 2 3 2 1 3 2 3 3 4 0.298 0.725 1 1 0.9859 6753074 11773 Ap2m1 2 5 4 4 6 5 6 7 5 0.294 1.032 1 0.6837 1 21312968 67437 Ssr3 6 7 4 2 4 6 6 4 9 0.294 1.014 1 0.7052 1 19923070 106529 Tecr 3 7 3 1 11 6 6 5 9 0.291 1.077 1 0.6321 1 85362701 333605 Frmpd4 0 0 0 0 0 0 0 0 2 0.291 0.456 1 1 0.9398 226246610 17158 Man2a1 2 0 1 1 5 1 1 3 5 0.284 0.605 1 1 0.9680 6755198 26443 Psma6 1 1 1 1 7 2 1 5 4 0.283 0.667 1 1 0.9778 88853588 54219 Cd320 0 0 0 0 0 0 2 0 0 0.272 0.425 1 1 0.9336 6678437 22070 Tpt1 7 11 9 7 17 11 12 16 14 0.270 1.384 0.8475 0.3322 1 15042957 19340 Rab3d 8 8 12 6 13 12 11 14 12 0.270 1.235 1 0.4637 1 6678137 20818 Srprb 6 7 7 6 16 9 7 14 14 0.268 1.242 1 0.4573 1 19527306 11534 Adk 15 16 18 11 27 19 19 26 27 0.267 1.740 0.4348 0.1231 1 21313640 71770 Ap2b1 0 0 0 1 0 1 0 2 0 0.267 0.415 1 1 0.9314 6678131 20810 Srm 6 7 6 4 13 8 8 10 11 0.265 1.128 1 0.5746 1 6755478 20382 Srsf2 1 2 2 2 1 2 1 2 3 0.265 0.473 1 1 0.9433 82950040 626683 Gm11362 0 2 1 0 1 1 0 1 3 0.265 0.467 1 1 0.9422 6753324 12466 Cct6a 2 2 4 2 9 3 4 5 8 0.260 0.793 1 0.9629 0.9938 124430755 73656 Ms4a6c 0 0 0 0 0 0 0 0 2 0.260 0.392 1 1 0.9268 13385318 66913 Kdelr2 1 0 0 0 1 1 0 1 2 0.259 0.419 1 1 0.9322 6679012 17955 Nap1l4 0 0 1 0 0 1 0 0 2 0.257 0.366 1 1 0.9215 29293809 104112 Acly 4 3 5 1 6 4 3 7 6 0.256 0.793 1 0.9629 0.9938 7242181 18807 Pld3 1 0 0 0 0 0 0 0 2 0.255 0.376 1 1 0.9236 8393156 53895 Clpp 1 0 1 0 2 0 0 2 2 0.253 0.430 1 1 0.9346 13385472 67115 Rpl14 11 14 8 7 14 13 12 18 13 0.252 1.322 0.9597 0.3834 1 13384718 66105 Ube2d3 0 0 0 0 0 1 2 1 0 0.251 0.354 1 1 0.9192 6680988 12861 Cox6a1 0 0 0 0 2 1 0 3 0 0.250 0.438 1 1 0.9363 309266474 434401 Gm5616 0 0 0 0 2 0 0 2 2 0.250 0.427 1 1 0.9338 6678467 22145 Tuba4a 30 34 38 20 31 30 35 45 46 0.248 2.107 0.2072 0.0284 1 115270960 29810 Bag3 0 0 0 0 1 0 0 2 1 0.248 0.365 1 1 0.9213 13384778 66171 Pgls 4 6 4 3 17 7 8 9 11 0.245 1.043 1 0.6714 1 160298219 14871 Gstt1 1 2 2 0 3 2 3 2 2 0.245 0.534 1 1 0.9555 94402184 668830 Gm9386 0 0 0 0 0 0 0 0 2 0.245 0.344 1 1 0.9172 229577281 56207 Uchl5 1 1 0 0 1 1 1 0 2 0.241 0.345 1 1 0.9175 254540082 19172 Psmb4 1 2 3 2 2 2 2 3 3 0.239 0.522 1 1 0.9532 167234372 75705 Eif4b 2 0 2 3 8 1 4 5 6 0.237 0.700 1 1 0.9826 258547102 74126 Syvn1 0 1 0 0 1 0 2 1 0 0.236 0.361 1 1 0.9205 165377173 57317 Srsf4 0 0 0 0 0 0 0 0 2 0.236 0.343 1 1 0.9170 6753618 13202 Ddt 6 5 4 4 8 5 6 9 7 0.235 0.814 1 0.9379 0.9961 10946972 59042 Cope 0 0 1 0 7 0 0 3 6 0.235 0.543 1 1 0.9570 226958579 219189 1300010F03Rik 0 0 0 0 1 0 0 0 2 0.235 0.352 1 1 0.9187 116089273 14569 Gdi2 10 12 13 8 24 12 13 21 22 0.233 1.349 0.9092 0.3599 1 170671724 78610 Uvrag 3 2 3 1 4 0 2 5 5 0.233 0.596 1 1 0.9664 126090932 67134 Nop56 1 1 1 1 7 2 2 3 4 0.233 0.539 1 1 0.9562 269954677 97541 Qars 4 5 3 3 13 5 6 8 10 0.231 0.855 1 0.8913 1.0000 377833476 100861916 LOC100861916 0 0 2 0 2 2 3 0 0 0.231 0.434 1 1 0.9355 7106389 26444 Psma7 1 2 2 1 4 1 2 3 4 0.230 0.524 1 1 0.9535 13386120 52530 Nhp2 1 0 1 0 0 0 2 0 1 0.230 0.346 1 1 0.9175 61740637 216860 Neurl4 0 0 0 0 1 2 0 0 0 0.229 0.361 1 1 0.9205 41282022 12321 Calu 0 0 0 0 1 0 0 0 2 0.229 0.323 1 1 0.9134 6755204 19173 Psmb5 0 1 2 1 3 0 0 2 4 0.227 0.431 1 1 0.9346 76881807 20701 Serpina1b 0 0 0 0 1 0 1 2 1 0.227 0.342 1 1 0.9170 6755698 20932 Surf4 5 7 5 3 9 7 7 7 8 0.226 0.852 1 0.8958 0.9996 6678768 17118 Marcks 1 1 2 1 2 1 1 2 3 0.226 0.426 1 1 0.9336 21313476 66397 Sar1b 2 1 1 0 7 1 2 2 7 0.225 0.565 1 1 0.9611 31543902 53382 Txnl1 0 1 0 0 4 1 0 4 2 0.225 0.458 1 1 0.9403 47894398 326618 Tpm4 1 1 1 0 2 1 2 1 2 0.225 0.368 1 1 0.9218 162287142 12894 Cpt1a 0 0 0 0 0 0 0 1 2 0.225 0.353 1 1 0.9190 Diabetes Page 44 of 73

33563282 26440 Psma1 0 1 0 0 2 1 0 0 3 0.223 0.387 1 1 0.9257 31712002 234699 Edc4 0 0 0 0 0 0 0 0 2 0.223 0.340 1 1 0.9165 146260280 15384 Hnrnpab 0 0 1 2 3 0 4 2 1 0.221 0.465 1 1 0.9417 9790169 18824 Plp2 1 1 1 1 2 1 1 2 2 0.221 0.383 1 1 0.9249 18034769 69178 Snx5 1 0 1 0 0 1 0 0 2 0.221 0.325 1 1 0.9138 238637277 17254 Slc3a2 16 20 14 9 27 16 18 26 26 0.220 1.431 0.7680 0.2963 1 124487358 75471 1700009N14Rik 6 5 7 5 9 5 8 10 9 0.220 0.907 1 0.8313 1 86198327 70769 Nolc1 0 2 2 0 2 2 2 1 3 0.220 0.392 1 1 0.9268 93102415 14450 Gart 1 2 1 0 1 2 1 1 2 0.219 0.361 1 1 0.9205 254826698 216456 Gls2 0 0 0 0 0 0 0 1 2 0.219 0.341 1 1 0.9167 47059143 234388 Ccdc124 0 1 1 0 1 2 0 1 1 0.219 0.311 1 1 0.9113 29825825 217310 C630004H02Rik 2 2 0 0 0 2 2 0 2 0.218 0.403 1 1 0.9289 13386092 68184 Denr 0 0 1 0 1 0 0 1 2 0.218 0.350 1 1 0.9185 20806532 56449 Csda 1 0 1 1 2 3 0 1 1 0.217 0.357 1 1 0.9197 114326446 17886 Myh9 18 20 19 18 41 23 20 28 45 0.216 1.576 0.5769 0.2031 1 19705578 11966 Atp6v1b2 2 2 0 1 7 0 3 7 2 0.216 0.519 1 1 0.9524 31543730 11416 Slc33a1 1 0 2 0 0 1 1 2 2 0.216 0.374 1 1 0.9231 100815972 14590 Ggh 8 13 5 6 18 12 9 14 14 0.215 1.071 1 0.6396 1 254553372 105148 Iars 7 8 8 1 25 5 7 17 19 0.214 1.119 1 0.5848 1 9845257 50708 Hist1h1c 6 6 6 0 0 0 6 7 6 0.214 0.664 1 1 0.9776 240848573 72162 Dhx36 0 0 0 0 0 2 0 0 0 0.214 0.329 1 1 0.9143 21450291 230163 Aldob 0 0 0 0 0 2 1 0 1 0.214 0.324 1 1 0.9136 7949018 12539 Cdc37 1 0 0 0 0 0 0 2 0 0.212 0.337 1 1 0.9158 6754576 17063 Muc13 0 0 0 0 0 2 0 0 0 0.212 0.314 1 1 0.9120 27229036 67398 Srpr 9 15 16 9 31 14 17 19 28 0.211 1.285 1 0.4163 1 13385054 66495 Ndufb3 0 2 1 2 2 1 1 3 3 0.211 0.431 1 1 0.9346 12584986 65019 Rpl23 15 17 19 14 23 17 21 23 25 0.210 1.382 0.8504 0.3332 1 31982072 19363 Rad51l1 0 0 0 0 0 0 0 2 0 0.209 0.312 1 1 0.9116 46485467 217116 Spata20 0 0 0 0 0 2 0 0 0 0.209 0.300 1 1 0.9094 158966704 20055 Rps16 15 33 18 15 36 27 28 29 33 0.207 1.598 0.5538 0.1907 1 19745150 109754 Cyb5r3 7 8 7 5 13 7 9 13 10 0.207 0.943 1 0.7893 1 13128964 11891 Rab27a 1 0 1 1 2 1 0 2 2 0.206 0.367 1 1 0.9218 33469023 74195 Elp3 2 0 0 0 0 0 0 0 3 0.206 0.343 1 1 0.9172 158966670 11749 Anxa6 14 21 16 13 34 20 18 29 30 0.205 1.466 0.7144 0.2712 1 6677905 20340 Glg1 4 5 5 4 5 6 5 6 6 0.205 0.692 1 1 0.9815 6678760 18777 Lypla1 1 1 1 0 2 0 1 2 2 0.205 0.322 1 1 0.9134 84871986 14775 Gpx1 1 2 2 1 4 1 3 2 4 0.204 0.451 1 1 0.9387 34328209 23917 Impdh1 0 0 0 0 3 1 0 2 3 0.204 0.378 1 1 0.9239 262263372 269378 Ahcy 42 61 50 30 74 60 63 65 66 0.202 2.421 0.0412 0.0059 1 27754071 67732 Iah1 0 0 0 1 4 0 2 0 4 0.202 0.392 1 1 0.9268 21313536 78920 Dlst 4 5 8 4 11 6 9 9 7 0.200 0.809 1 0.9438 0.9956 31980922 55949 Eef1b2 14 15 14 10 22 20 17 18 18 0.199 1.250 1 0.4484 1 6678439 22072 Prss2 18 20 18 19 30 20 24 28 31 0.198 1.502 0.6636 0.2476 1 27532959 107747 Aldh1l1 24 22 27 16 42 25 30 33 39 0.197 1.601 0.5515 0.1893 1 19526878 69051 Pycr2 2 8 3 2 14 4 5 8 11 0.197 0.721 1 1 0.9852 33468897 14629 Gclc 0 0 0 0 0 0 0 0 2 0.195 0.293 1 1 0.9084 6678682 16852 Lgals1 9 10 6 5 13 9 11 10 12 0.194 0.893 1 0.8483 1 15617197 66290 Atp6v1g1 1 1 0 0 2 1 1 2 2 0.194 0.326 1 1 0.9138 31982030 192662 Arhgdia 3 4 3 2 12 5 4 7 7 0.192 0.693 1 1 0.9815 171543886 18478 Pah 7 5 6 5 5 6 7 7 7 0.192 0.682 1 1 0.9801 85701716 105418 E330034G19Rik 0 0 1 0 0 0 1 1 2 0.192 0.291 1 1 0.9081 13385916 67868 Cela3b 49 71 55 45 86 67 72 76 82 0.190 2.313 0.0803 0.0103 1 38371755 69219 Ddah1 0 0 0 0 0 0 0 0 2 0.190 0.289 1 1 0.9077 172072593 26885 Casp8ap2 0 0 0 1 0 1 0 0 2 0.189 0.278 1 1 0.9062 38348570 381798 4930590J08Rik 0 0 0 0 1 0 0 1 2 0.187 0.287 1 1 0.9076 309263329 383080 Gm5218 13 12 12 0 7 10 12 12 9 0.186 0.896 1 0.8437 1 225543319 269523 Vcp 33 38 36 23 65 40 39 50 61 0.185 1.855 0.3544 0.0821 1 6677799 20054 Rps15 8 10 12 0 21 10 10 14 16 0.185 0.894 1 0.8468 1 160333923 51810 Hnrnpu 6 3 6 3 9 4 7 9 6 0.185 0.661 1 1 0.9770 23821025 56430 Clip1 1 0 1 1 1 0 1 1 2 0.185 0.291 1 1 0.9081 254939710 330863 Trim67 0 0 0 0 0 0 2 0 0 0.185 0.270 1 1 0.9051 Page 45 of 73 Diabetes

126723461 12469 Cct8 5 8 9 3 15 4 6 14 14 0.184 0.839 1 0.9109 0.9984 14149756 67204 Eif2s2 7 5 6 6 10 9 7 11 6 0.184 0.758 1 1 0.9900 39930413 269966 Nup98 0 0 0 1 0 0 0 0 2 0.184 0.276 1 1 0.9060 6754220 15382 Hnrnpa1 4 0 5 0 6 3 4 5 4 0.182 0.533 1 1 0.9552 157951725 12386 Ctnna2 0 1 1 0 0 2 1 0 0 0.182 0.286 1 1 0.9074 124244040 78655 Eif3j 5 7 7 4 11 7 5 11 9 0.181 0.749 1 1 0.9889 42415473 19055 Ppp3ca 0 0 0 0 3 0 0 3 2 0.180 0.306 1 1 0.9105 6754254 15519 Hsp90aa1 9 27 26 17 41 25 23 34 32 0.178 1.424 0.7786 0.3011 1 31981310 27061 Bcap31 3 5 3 2 9 4 4 5 8 0.178 0.569 1 1 0.9618 19526986 109900 Asl 6 7 7 2 17 6 8 10 13 0.176 0.777 1 0.9803 0.9921 12963571 66416 Ndufa7 2 3 2 2 4 2 3 3 4 0.173 0.453 1 1 0.9392 228480228 68416 Sycn 9 9 9 7 13 12 9 12 11 0.172 0.797 1 0.9585 0.9942 164698417 223770 Brd1 7 8 6 3 0 7 0 7 8 0.172 0.587 1 1 0.9651 110630015 13690 Eif4g2 0 1 0 0 0 0 0 2 1 0.172 0.253 1 1 0.9030 56550071 76703 Cpb1 91 93 93 78 122 107 116 112 118 0.171 2.533 0.0216 0.0032 1 30519911 21346 Tagln2 6 6 9 3 19 7 8 11 15 0.171 0.823 1 0.9289 0.9969 13384886 109791 Clps 32 35 35 24 49 40 40 38 49 0.170 1.475 0.7017 0.2658 1 21361209 97122 Hist2h4 17 20 17 15 24 20 20 23 25 0.170 1.152 1 0.5489 1 29789199 70572 Ipo5 2 2 4 0 7 2 3 5 5 0.169 0.432 1 1 0.9349 8567338 54161 Copg 9 20 10 12 32 15 17 18 29 0.168 1.093 1 0.6127 1 39930335 224742 Abcf1 2 4 7 4 10 3 5 8 9 0.165 0.597 1 1 0.9667 6755392 20200 S100a6 4 3 4 3 4 4 5 3 5 0.165 0.505 1 1 0.9496 149363634 217057 Ptrh2 1 5 2 2 8 3 4 5 5 0.165 0.463 1 1 0.9414 339895913 11764 Ap1b1 2 2 3 1 7 0 4 0 8 0.165 0.431 1 1 0.9346 7110705 19231 Ptma 6 6 5 0 9 5 6 7 7 0.164 0.594 1 1 0.9662 6681095 13063 Cycs 3 7 4 2 9 4 6 6 8 0.164 0.565 1 1 0.9611 149234297 100042740 Rpl31-ps9 17 19 21 18 26 23 24 21 26 0.161 1.113 1 0.5921 1 171906557 18600 Padi2 1 2 3 0 8 2 2 4 6 0.161 0.397 1 1 0.9279 160707956 11750 Anxa7 2 3 5 2 4 2 2 7 4 0.160 0.444 1 1 0.9373 167716840 5912281 COX2 7 10 8 7 13 9 9 11 13 0.156 0.719 1 1 0.9851 18079341 68135 Eif3h 3 6 5 2 14 5 5 9 9 0.156 0.594 1 1 0.9662 140969946 78330 Ndufv3 0 0 0 1 3 0 0 2 3 0.156 0.284 1 1 0.9070 124486883 218343 Ttc37 0 0 0 0 1 0 0 0 2 0.156 0.235 1 1 0.9011 7305395 18950 Pnp 2 4 3 2 6 4 4 4 4 0.155 0.456 1 1 0.9398 6680720 11843 Arf4 6 7 7 4 10 5 6 9 11 0.153 0.581 1 1 0.9639 309262274 100504157 Gm20091 2 2 2 0 2 2 2 2 2 0.153 0.304 1 1 0.9102 148806863 544696 D630037F22Rik 0 0 0 0 1 0 0 0 2 0.153 0.230 1 1 0.9007 22165384 227613 Tubb4b 7 8 9 7 12 8 10 10 12 0.152 0.693 1 1 0.9815 340139459 12462 Cct3 3 4 4 1 13 2 3 9 9 0.152 0.496 1 1 0.9478 8394325 50934 Slc7a8 1 2 1 1 4 1 1 2 4 0.152 0.315 1 1 0.9120 22094075 11740 Slc25a5 29 38 27 18 53 35 37 39 41 0.150 1.299 1 0.4032 1 148540106 17850 Mut 3 5 4 1 12 3 4 8 8 0.150 0.532 1 1 0.9550 285402638 107702 Rnh1 23 25 23 19 49 25 26 35 43 0.148 1.246 1 0.4522 1 6755368 20084 Rps18 21 21 20 18 30 24 19 29 30 0.148 1.053 1 0.6608 1 309268181 433745 Gm12816 2 2 3 2 3 3 4 3 1 0.148 0.343 1 1 0.9170 33504483 76846 Rps9 29 35 29 22 36 31 31 40 36 0.144 1.207 1 0.4926 1 46560565 69608 Sec24d 6 5 6 2 20 6 7 11 12 0.144 0.600 1 1 0.9673 84781781 231887 Pdap1 0 1 2 1 6 0 1 4 4 0.144 0.325 1 1 0.9138 13385036 66480 Rpl15 20 22 20 13 28 24 20 25 26 0.142 0.954 1 0.7768 1 21312406 72141 Adpgk 1 2 2 1 7 1 2 4 5 0.142 0.354 1 1 0.9192 126032329 13627 Eef1a1 61 91 63 60 143 75 84 102 126 0.140 2.041 0.2449 0.0381 1 6755911 22166 Txn1 8 10 11 6 9 10 10 11 9 0.140 0.661 1 1 0.9770 14192922 11464 Actc1 8 7 7 6 12 8 8 10 11 0.140 0.581 1 1 0.9639 9506983 19052 Ppp2ca 1 3 1 1 4 1 2 3 3 0.140 0.285 1 1 0.9072 19527228 52637 Cisd1 1 1 1 1 4 1 0 2 3 0.140 0.260 1 1 0.9038 28372479 75617 Rps25 14 16 13 10 19 15 14 19 18 0.139 0.801 1 0.9526 0.9948 311893374 13427 Dync1i2 1 1 3 0 5 2 3 2 3 0.139 0.317 1 1 0.9122 113866024 19345 Rab5c 2 1 3 1 6 3 1 3 5 0.138 0.334 1 1 0.9153 74315975 70247 Psmd1 1 1 1 1 5 1 2 3 2 0.138 0.283 1 1 0.9070 16418339 110954 Rpl10 12 18 15 10 21 11 16 20 23 0.137 0.787 1 0.9702 0.9931 110625979 67160 Eef1g 22 29 20 20 41 29 25 34 34 0.134 1.107 1 0.5979 1 Diabetes Page 46 of 73

34996495 20014 Rpn2 17 32 19 14 47 22 25 33 38 0.132 1.071 1 0.6381 1 31980744 27425 Atp5l 1 2 2 0 7 2 2 3 5 0.132 0.332 1 1 0.9150 54312076 109697 Cpa1 72 74 78 53 90 70 84 85 94 0.131 1.716 0.4526 0.1331 1 160333840 66384 Srp19 2 3 2 1 6 2 3 3 5 0.131 0.324 1 1 0.9136 118403322 66948 Acad8 0 2 2 2 4 2 3 1 4 0.131 0.298 1 1 0.9092 41054806 14678 Gnai2 0 0 0 0 1 0 0 1 1 0.131 0.184 0.9107 1 0.8986 149262567 100043184 Gm11703 0 0 9 0 0 9 0 0 0 0.130 0.323 1 1 0.9134 56699432 208643 Eif4g1 15 15 18 7 28 12 14 25 24 0.127 0.755 1 1 0.9896 160298209 14718 Got1 5 3 5 2 11 5 5 4 10 0.127 0.447 1 1 0.9379 116325999 14859 Gsta3 4 3 6 2 7 4 4 5 7 0.127 0.442 1 1 0.9371 6681297 13706 Cela2a 52 63 51 47 87 58 62 80 70 0.125 1.480 0.6937 0.2614 1 259155334 217615 Ctage5 3 3 5 1 7 3 4 5 5 0.125 0.362 1 1 0.9208 165377206 107513 Ssr1 10 12 10 10 17 12 12 14 16 0.124 0.642 1 1 0.9742 13399310 67097 Rps10 23 33 35 25 54 30 25 45 54 0.123 1.107 1 0.5979 1 6755040 18643 Pfn1 8 14 12 9 16 12 13 13 15 0.123 0.666 1 1 0.9778 6678105 20730 Spink3 10 10 8 5 7 13 8 7 8 0.123 0.557 1 1 0.9596 13384864 66269 Tmed6 3 5 4 3 8 4 4 6 7 0.123 0.406 1 1 0.9295 70778915 17698 Msn 0 0 3 0 5 0 0 4 4 0.120 0.258 1 1 0.9035 33859811 97212 Hadha 12 24 14 8 34 12 17 26 28 0.119 0.782 1 0.9745 0.9927 31542143 11848 Rhoa 6 5 6 5 8 6 7 7 7 0.119 0.424 1 1 0.9333 33859640 21351 Taldo1 13 13 11 8 13 10 15 14 13 0.118 0.617 1 1 0.9700 37700232 18102 Nme1 7 6 3 5 11 8 6 7 8 0.117 0.446 1 1 0.9379 13384620 15387 Hnrnpk 10 8 12 7 26 8 12 18 19 0.115 0.655 1 1 0.9760 6681069 13007 Csrp1 4 5 7 3 10 5 5 6 10 0.115 0.403 1 1 0.9289 162461907 15526 Hspa9 19 23 25 19 38 24 27 26 34 0.114 0.885 1 0.8576 1 6754994 23983 Pcbp1 7 5 7 4 12 7 7 8 9 0.114 0.471 1 1 0.9430 359385696 22631 Ywhaz 17 19 18 16 25 19 19 22 25 0.113 0.696 1 1 0.9821 255069715 66988 Lap3 5 4 6 4 21 5 6 10 15 0.113 0.491 1 1 0.9467 19526884 69080 Gmppa 3 3 1 1 5 1 3 4 4 0.113 0.274 1 1 0.9057 227116327 21894 Tln1 0 2 0 0 4 0 1 2 4 0.111 0.228 1 1 0.9006 67010039 232680 Cpa2 25 31 28 19 44 29 31 35 37 0.110 0.920 1 0.8158 1 6680121 14863 Gstm2 15 17 15 14 29 16 19 21 25 0.110 0.703 1 1 0.9830 6754508 16796 Lasp1 2 1 3 1 5 1 1 4 5 0.110 0.261 1 1 0.9040 21313618 66075 Chchd3 5 6 6 2 10 5 6 7 8 0.109 0.422 1 1 0.9330 165932341 109901 Cela1 65 63 65 59 99 71 78 83 82 0.108 1.433 0.7645 0.2944 1 6755358 26961 Rpl8 17 21 19 15 27 20 19 24 26 0.107 0.770 1 0.9875 0.9913 149250385 100046034 Gm14279 17 25 24 15 24 22 26 25 21 0.107 0.746 1 1 0.9884 254553458 14751 Gpi1 12 18 16 7 26 15 13 19 23 0.107 0.675 1 1 0.9789 112293266 15525 Hspa4 1 3 1 1 13 4 2 5 6 0.107 0.303 1 1 0.9100 33859686 66681 Pgm1 7 5 5 3 8 5 4 6 10 0.106 0.390 1 1 0.9263 13654268 22122 Tsta3 1 2 3 0 9 4 3 3 4 0.106 0.287 1 1 0.9076 210032861 69736 Nup37 1 2 0 2 0 0 0 3 0 0.106 0.184 0.9110 1 0.8986 6671569 11837 Rplp0 24 28 23 21 32 25 28 30 30 0.105 0.797 1 0.9570 0.9944 15426055 70349 Copb1 14 15 13 9 28 8 13 22 27 0.105 0.627 1 1 0.9717 27229028 67133 Gp2 12 10 16 12 14 13 14 13 17 0.104 0.586 1 1 0.9648 31981515 19989 Rpl7 38 38 43 32 43 41 39 47 45 0.103 0.973 1 0.7534 1 309268560 639606 Gm10420 19 30 1 18 39 25 0 33 35 0.103 0.717 1 1 0.9849 47271535 217337 Srp68 17 18 20 12 32 22 20 21 25 0.103 0.685 1 1 0.9804 6753944 14431 Gamt 6 11 8 6 12 8 8 10 12 0.102 0.463 1 1 0.9414 283806681 192196 Luc7l2 0 2 1 0 2 2 0 1 2 0.102 0.192 0.9302 1 0.8987 27229277 110960 Tars 7 13 15 8 31 11 13 17 24 0.101 0.595 1 1 0.9664 31981962 21785 Tff2 1 1 2 2 2 2 1 2 2 0.101 0.201 0.9513 1 0.8990 13386034 68052 Rps13 20 22 23 20 31 21 23 30 29 0.100 0.745 1 1 0.9884 29789080 50797 Copb2 13 23 26 12 47 21 21 35 31 0.100 0.690 1 1 0.9812 16716353 20168 Rtn3 1 0 2 2 3 2 2 2 2 0.100 0.210 0.9737 1 0.8993 319402143 100503605 Beta-s 43 54 40 34 67 44 55 57 55 0.099 1.066 1 0.6441 1 19072792 76299 Erp44 8 5 11 4 17 7 8 12 12 0.098 0.449 1 1 0.9384 171906578 19359 Rad23b 9 10 8 5 11 8 9 11 10 0.098 0.421 1 1 0.9325 10181184 57423 Atp5j2 2 2 2 1 3 2 2 3 2 0.097 0.205 0.9614 1 0.8992 31981690 15481 Hspa8 34 44 39 32 64 41 45 47 55 0.096 0.963 1 0.7643 1 51491845 67300 Cltc 20 25 27 20 60 23 26 36 49 0.096 0.820 1 0.9319 0.9966 Page 47 of 73 Diabetes

148747558 21672 Prdx2 13 15 14 11 20 14 15 16 19 0.096 0.562 1 1 0.9606 78214312 11950 Atp5f1 16 14 15 8 16 16 12 15 18 0.096 0.544 1 1 0.9572 30841021 66251 Arfgap3 3 5 5 3 7 3 4 5 8 0.096 0.314 1 1 0.9120 9789997 56384 Letm1 0 1 0 1 5 0 0 3 3 0.095 0.192 0.9295 1 0.8987 38348230 67475 Ero1lb 31 36 29 24 47 30 35 40 41 0.094 0.795 1 0.9600 0.9941 309264544 100504988 LOC100504988 5 5 6 6 6 6 6 6 7 0.094 0.322 1 1 0.9134 162417975 15926 Idh1 8 8 10 3 14 7 7 10 13 0.093 0.422 1 1 0.9327 255069795 22321 Vars 27 19 30 16 53 22 24 40 41 0.092 0.772 1 0.9861 0.9915 6680924 12631 Cfl1 11 9 13 8 26 11 12 16 19 0.092 0.517 1 1 0.9522 149258501 100046151 LOC100046151 14 16 16 10 22 14 14 20 20 0.091 0.531 1 1 0.9547 111154076 13518 Dst 0 0 4 0 0 4 0 0 0 0.091 0.171 0.8804 1 0.8986 326381098 20226 Sars 9 15 14 9 19 11 11 18 18 0.090 0.506 1 1 0.9499 13384608 13180 Pcbd1 7 7 8 6 10 7 8 8 11 0.090 0.373 1 1 0.9228 71043961 67373 2210010C04Rik 69 70 61 44 90 71 71 72 77 0.089 1.135 1 0.5675 1 31543976 22628 Ywhag 8 5 9 6 15 8 7 11 11 0.089 0.407 1 1 0.9298 56744242 11765 Ap1g1 1 1 2 0 2 1 2 0 2 0.088 0.161 0.8598 1 0.8989 6756039 22630 Ywhaq 5 4 7 3 12 4 6 8 9 0.087 0.328 1 1 0.9143 282398108 103963 Rpn1 52 64 56 45 70 56 63 58 72 0.086 0.977 1 0.7487 1 21704162 22192 Ube2m 1 2 1 0 3 0 0 2 3 0.085 0.154 0.8448 1 0.8992 110625811 73137 Prrc1 1 2 0 0 10 2 0 3 7 0.083 0.210 0.9732 1 0.8993 21703842 28088 D10Wsu52e 2 5 7 3 8 4 4 6 8 0.082 0.275 1 1 0.9058 18859597 68197 Ndufc2 2 2 3 3 5 3 3 3 4 0.082 0.222 1 1 0.9002 6679587 19324 Rab1 18 19 16 13 16 17 18 16 21 0.081 0.545 1 1 0.9575 356582477 18293 Ogdh 5 6 4 2 15 5 3 9 11 0.081 0.313 1 1 0.9116 38372905 17274 Rab8a 1 1 2 0 4 1 1 3 3 0.081 0.161 0.8608 1 0.8989 262359885 276770 Eif5a 19 22 22 19 28 22 23 26 25 0.080 0.590 1 1 0.9655 16716381 85305 Kars 10 16 12 7 28 14 12 19 19 0.080 0.461 1 1 0.9409 31791059 11658 Alcam 1 1 1 2 2 2 1 2 1 0.080 0.144 0.8265 1 0.8998 161016824 18041 Nfs1 0 0 0 0 1 0 0 0 0 0.080 0.114 0.7732 1 0.9030 8567400 19942 Rpl27 12 11 11 9 21 12 13 14 16 0.079 0.419 1 1 0.9322 93102409 14104 Fasn 5 5 9 3 14 5 4 13 9 0.079 0.320 1 1 0.9129 13430890 50709 Hist1h1e 4 3 3 3 3 3 4 4 3 0.079 0.206 0.9627 1 0.8992 30794450 67891 Rpl4 41 45 49 42 62 41 48 57 60 0.078 0.806 1 0.9482 0.9952 225007607 66074 Tmem167 2 1 2 1 2 2 1 2 2 0.077 0.152 0.8422 1 0.8993 71774133 19035 Ppib 46 58 49 40 65 50 54 60 57 0.075 0.801 1 0.9541 0.9946 33859514 12036 Bcat2 17 16 16 12 23 16 17 19 20 0.075 0.493 1 1 0.9473 6753490 26891 Cops4 1 0 1 0 2 1 0 1 2 0.075 0.124 0.7897 1 0.9016 224994260 16785 Rpsa 20 23 19 19 37 24 22 29 27 0.074 0.538 1 1 0.9560 6755965 22334 Vdac2 10 12 16 12 21 14 13 18 16 0.074 0.431 1 1 0.9346 255708437 18707 Pik3cd 0 0 0 0 0 1 0 0 0 0.074 0.109 0.7653 1 0.9036 72534792 110350 Dync2h1 0 0 0 0 1 0 0 0 0 0.074 0.107 0.7622 1 0.9040 114158675 66222 Serpinb1a 32 35 49 35 51 33 37 52 52 0.072 0.682 1 1 0.9801 166851828 66043 Atp5d 2 4 3 2 6 3 4 3 5 0.072 0.205 0.9619 1 0.8992 150010641 667736 Gm8787 0 1 1 0 0 1 0 0 0 0.072 0.096 0.7464 1 0.9058 254675270 20103 Rps5 24 33 31 22 34 30 28 32 33 0.071 0.607 1 1 0.9684 84875537 17975 Ncl 15 20 17 10 23 20 14 18 22 0.071 0.439 1 1 0.9363 161016820 13437 Dnpep 7 6 9 4 21 7 7 12 14 0.071 0.305 1 1 0.9102 31543940 56491 Vapb 5 4 5 1 5 3 4 7 3 0.071 0.220 0.9986 1 0.9000 51172612 14473 Gc 1 3 3 0 4 2 3 2 3 0.071 0.166 0.8712 1 0.8987 25742730 19951 Rpl32 5 8 5 5 11 5 5 10 9 0.070 0.275 1 1 0.9057 225637531 66085 Eif3f 1 3 3 3 6 2 0 4 7 0.070 0.194 0.9331 1 0.8987 160333789 20751 Spr 0 1 1 1 4 0 1 2 3 0.070 0.131 0.8012 1 0.9009 122939192 12757 Clta 1 0 2 2 1 1 1 2 2 0.070 0.116 0.7758 1 0.9026 157951706 12282 Hyou1 44 54 47 30 100 53 49 63 71 0.069 0.803 1 0.9512 0.9949 33859604 19181 Psmc2 1 1 4 2 6 0 0 5 5 0.068 0.168 0.8750 1 0.8987 13384674 66042 Sostdc1 1 1 2 0 2 1 1 1 3 0.067 0.114 0.7730 1 0.9030 345842335 380698 Obscn 0 0 0 0 0 0 1 1 1 0.066 0.094 0.7427 1 0.9062 16716597 114664 Hsd17b11 1 0 0 0 1 0 0 1 1 0.066 0.091 0.7385 1 0.9068 124286826 225363 Etf1 6 7 7 5 14 7 8 9 9 0.065 0.286 1 1 0.9074 40807498 15473 Hrsp12 2 3 2 1 7 3 1 4 5 0.065 0.177 0.8948 1 0.8985 21728370 67006 Cisd2 1 3 1 1 9 2 3 3 5 0.065 0.158 0.8533 1 0.8990 Diabetes Page 48 of 73

25092662 28084 Vps25 0 0 1 0 1 0 0 0 1 0.065 0.093 0.7420 1 0.9062 124486712 81910 Rrbp1 210 222 250 147 276 220 237 237 249 0.064 1.465 0.7160 0.2721 1 33859482 13629 Eef2 107 123 102 91 177 116 115 135 145 0.064 1.093 1 0.6142 1 268837785 319322 Sf3b2 0 0 0 0 1 0 0 0 0 0.064 0.085 0.7305 1 0.9081 6753078 11777 Ap3s1 1 0 0 0 1 0 0 0 0 0.063 0.090 0.7380 1 0.9068 117606270 18103 Nme2 21 17 14 10 27 17 16 20 23 0.062 0.399 1 1 0.9281 6753178 23825 Banf1 1 1 1 1 3 0 1 2 2 0.062 0.114 0.7734 1 0.9028 111607467 109959 Amy2a5 150 170 180 139 87 176 193 63 186 0.061 1.183 1 0.5169 1 133778951 16433 Cuzd1 9 7 13 4 19 9 9 12 14 0.061 0.295 1 1 0.9088 62460366 69202 Ptms 3 2 2 3 6 4 2 3 5 0.061 0.165 0.8695 1 0.8987 115647930 238568 Serpinb6d 0 0 0 0 0 0 1 0 0 0.061 0.088 0.7346 1 0.9073 160333829 55988 Snx12 0 0 0 0 0 0 0 1 1 0.061 0.088 0.7344 1 0.9073 158635979 11938 Atp2a2 28 30 33 23 62 28 33 39 50 0.060 0.566 1 1 0.9613 21553309 246703 Apoa1bp 0 1 0 0 3 1 1 3 1 0.060 0.106 0.7602 1 0.9042 13384796 66191 Ier3ip1 0 0 0 0 1 0 0 0 1 0.059 0.085 0.7303 1 0.9081 54287684 66656 Eef1d 15 17 19 14 29 16 19 23 23 0.058 0.385 1 1 0.9252 148728175 93887 Pcdhb16 0 0 0 0 1 0 0 0 0 0.058 0.083 0.7286 1 0.9084 149268895 100043876 Gm4705 18 19 19 14 16 22 19 14 18 0.057 0.376 1 1 0.9236 124430541 217869 Eif5 4 6 5 1 17 4 5 9 10 0.056 0.210 0.9732 1 0.8993 19527026 98238 Lrrc59 19 22 19 12 34 20 22 23 26 0.055 0.362 1 1 0.9205 21450277 11928 Atp1a1 7 6 11 8 20 8 9 15 12 0.054 0.261 1 1 0.9040 284172357 216443 Mars 0 0 2 0 8 1 2 3 5 0.054 0.135 0.8097 1 0.9004 23956334 227638 Qsox2 1 1 1 0 2 2 0 1 0 0.054 0.083 0.7277 1 0.9084 113865835 78651 Lsm6 0 0 0 0 0 0 0 0 1 0.053 0.078 0.7212 1 0.9095 31981400 23874 Farsb 8 13 9 5 24 7 9 16 19 0.052 0.264 1 1 0.9043 6680932 12652 Chga 0 1 0 0 3 3 1 0 1 0.052 0.091 0.7383 1 0.9068 10946940 59021 Rab2a 7 8 7 6 14 7 7 10 11 0.051 0.223 1 1 0.9003 33859662 26949 Vat1 4 3 6 4 6 2 4 8 6 0.050 0.162 0.8623 1 0.8988 117938332 20742 Spnb2 2 0 1 1 8 1 2 1 7 0.050 0.118 0.7801 1 0.9023 254281222 64704 Htra2 0 0 0 0 3 0 0 3 1 0.050 0.091 0.7385 1 0.9068 6678359 21881 Tkt 18 22 24 19 36 23 22 27 28 0.049 0.378 1 1 0.9239 22203755 56347 Eif3c 5 6 6 4 18 5 7 10 11 0.049 0.204 0.9592 1 0.8991 19882201 21762 Psmd2 5 2 4 3 8 4 3 5 7 0.049 0.154 0.8464 1 0.8991 7106387 26442 Psma5 2 1 2 1 5 1 0 3 4 0.049 0.121 0.7844 1 0.9020 31982764 20539 Slc7a5 1 0 3 2 4 1 2 3 3 0.049 0.107 0.7626 1 0.9040 116063531 12346 Car1 0 2 0 0 1 0 2 1 0 0.049 0.078 0.7220 1 0.9095 6754548 16885 Limk1 0 0 0 0 0 1 0 1 0 0.049 0.074 0.7163 1 0.9105 227330633 72157 Pgm2 1 2 1 2 7 1 2 4 4 0.048 0.114 0.7738 1 0.9028 23956110 20639 Snrpb2 1 0 0 0 0 0 1 0 0 0.048 0.064 0.7055 1 0.9128 13385408 67025 Rpl11 12 12 11 8 15 10 13 13 13 0.047 0.248 1 1 0.9024 37718983 77407 Rab35 0 0 0 0 1 0 0 0 0 0.047 0.071 0.7134 1 0.9111 23943876 69036 Zg16 24 24 25 23 31 23 30 25 28 0.046 0.351 1 1 0.9187 227500281 110842 Etfa 16 21 24 17 33 16 21 26 30 0.046 0.319 1 1 0.9127 6753036 11669 Aldh2 12 17 15 12 33 15 17 20 24 0.046 0.309 1 1 0.9109 309265997 667284 Gm8556 1 0 0 3 0 0 2 0 2 0.046 0.078 0.7215 1 0.9095 161484660 12892 Cpox 0 0 0 0 1 0 0 0 0 0.046 0.066 0.7078 1 0.9124 114145561 16691 Krt8 55 60 59 52 83 60 68 64 68 0.045 0.530 1 1 0.9547 6680836 12317 Calr 31 32 38 29 55 28 34 45 49 0.045 0.436 1 1 0.9357 45597447 20655 Sod1 12 17 19 12 23 17 17 17 19 0.045 0.282 1 1 0.9068 6671702 12465 Cct5 2 2 2 0 10 2 3 3 6 0.045 0.115 0.7747 1 0.9028 85861252 67812 Ubxn4 0 0 0 0 0 1 0 1 0 0.045 0.062 0.7034 1 0.9135 34328108 12842 Col1a1 11 11 15 13 24 16 13 13 20 0.044 0.256 1 1 0.9033 226442901 73158 Larp1 10 11 13 6 25 11 14 13 17 0.044 0.242 1 1 0.9018 31980844 52585 Dhrs1 5 8 7 4 12 4 5 9 12 0.044 0.171 0.8807 1 0.8986 33468853 14526 Gcg 0 2 1 1 3 0 0 3 2 0.044 0.083 0.7281 1 0.9084 124487019 319955 Ercc6 0 0 0 0 0 0 0 0 1 0.044 0.066 0.7070 1 0.9124 7657011 13194 Ddb1 0 0 1 1 0 0 0 0 0 0.044 0.063 0.7036 1 0.9135 121949765 21917 Tmpo 0 0 0 0 1 0 1 0 0 0.044 0.061 0.7020 1 0.9138 124487105 238247 Arid4a 0 0 0 0 1 0 0 0 0 0.044 0.061 0.7015 1 0.9138 124494242 17913 Myo1c 1 2 1 0 1 0 0 1 2 0.043 0.068 0.7095 1 0.9121 58037267 71853 Pdia6 23 28 27 21 46 25 25 36 35 0.042 0.326 1 1 0.9141 Page 49 of 73 Diabetes

22267442 67003 Uqcrc2 14 17 17 10 18 13 15 18 18 0.042 0.254 1 1 0.9030 16716467 94181 Nans 6 6 6 4 14 5 6 7 12 0.042 0.167 0.8720 1 0.8987 149266660 100041120 Gm3150 2 1 2 1 1 2 1 2 1 0.042 0.080 0.7239 1 0.9092 37360977 238988 Erc2 0 0 2 0 2 0 2 1 2 0.042 0.073 0.7159 1 0.9105 75677522 71609 Tradd 0 0 0 0 0 0 1 0 1 0.042 0.060 0.7002 1 0.9142 6677803 20090 Rps29 8 8 5 5 10 8 7 7 7 0.041 0.163 0.8646 1 0.8988 123702073 22317 Vamp1 0 1 0 1 0 1 1 0 0 0.041 0.059 0.6992 1 0.9145 6678407 21985 Tpd52 2 5 5 2 9 3 5 5 6 0.040 0.128 0.7966 1 0.9012 24762230 267019 Rps15a 15 15 16 10 25 15 15 16 22 0.039 0.239 1 1 0.9015 149250230 100043882 Gm14277 0 0 1 0 1 1 0 1 1 0.039 0.056 0.6963 1 0.9153 29171318 66162 Bola2 0 0 0 0 1 0 0 1 1 0.038 0.056 0.6967 1 0.9153 377833781 100048613 LOC100048613 0 0 0 1 0 0 0 0 0 0.038 0.054 0.6940 1 0.9161 145966911 67511 Tmed9 1 1 1 0 1 1 1 1 0 0.038 0.053 0.6933 1 0.9161 90186270 17756 Mtap2 0 0 0 0 2 0 0 0 2 0.037 0.059 0.6997 1 0.9142 268370114 68832 1110057K04Rik 0 1 0 0 1 0 0 1 1 0.037 0.053 0.6939 1 0.9161 25141233 17184 Matr3 0 0 0 0 0 0 0 0 1 0.037 0.052 0.6928 1 0.9161 149257598 100040298 Gm15501 26 27 27 20 34 24 26 30 30 0.036 0.276 1 1 0.9060 31981600 17991 Ndufa2 1 0 2 0 1 0 1 0 2 0.036 0.059 0.7000 1 0.9142 27369788 216724 Rufy1 0 0 0 0 1 0 0 1 0 0.036 0.051 0.6911 1 0.9168 19526956 73024 2900064A13Rik 1 0 1 0 1 0 1 0 1 0.036 0.050 0.6905 1 0.9168 71043953 83398 Ndst3 0 0 0 0 0 0 0 1 0 0.036 0.049 0.6897 1 0.9172 31982229 16548 Khk 1 0 0 0 0 0 0 0 0 0.036 0.048 0.6883 1 0.9176 148747410 213827 Arcn1 21 21 21 19 29 18 21 26 27 0.035 0.260 1 1 0.9040 13386054 68089 Arpc4 3 4 3 2 7 3 3 4 6 0.035 0.105 0.7593 1 0.9042 23956084 11370 Acadvl 0 0 1 1 14 0 0 5 8 0.035 0.097 0.7471 1 0.9058 159032062 11431 Acp1 1 2 2 0 1 1 1 2 2 0.035 0.061 0.7019 1 0.9138 6753060 11747 Anxa5 19 19 17 15 27 18 20 19 23 0.034 0.221 1 1 0.9001 85861218 229363 Gmps 0 0 0 0 0 0 1 0 0 0.034 0.051 0.6919 1 0.9164 40556608 15516 Hsp90ab1 30 35 32 24 51 34 30 39 40 0.033 0.305 1 1 0.9102 357588427 20700 Serpina1a 2 3 4 9 3 9 3 2 3 0.033 0.098 0.7489 1 0.9055 30519915 27973 Vkorc1 1 1 2 1 2 1 1 2 2 0.033 0.055 0.6958 1 0.9153 7305121 27357 Gyg 0 0 0 0 1 0 0 0 0 0.033 0.047 0.6879 1 0.9176 6754086 14866 Gstm5 0 0 0 0 1 0 0 0 1 0.033 0.047 0.6877 1 0.9176 21312658 68036 Zfp706 0 0 0 0 2 0 0 2 0 0.032 0.050 0.6906 1 0.9168 7305363 18472 Pafah1b1 0 0 0 0 1 0 0 0 1 0.032 0.048 0.6885 1 0.9176 112181182 12858 Cox5a 4 6 4 3 6 4 5 3 7 0.031 0.101 0.7528 1 0.9051 21312962 67456 Ergic2 0 0 0 0 1 0 0 0 0 0.030 0.045 0.6861 1 0.9184 164698448 105083 Pelo 0 0 0 0 1 0 0 0 0 0.030 0.043 0.6836 1 0.9193 157909799 245688 Rbbp7 0 1 1 0 1 0 0 0 0 0.030 0.042 0.6829 1 0.9193 13507612 28200 Dhrs4 1 1 1 0 1 0 0 0 0 0.030 0.041 0.6818 1 0.9197 163310765 11657 Alb 119 125 135 115 148 122 125 134 148 0.029 0.531 1 1 0.9547 19526880 69071 Tmem97 14 17 17 8 25 10 16 19 21 0.029 0.177 0.8957 1 0.8985 6755090 18778 Pla2g1b 3 4 5 3 7 2 4 5 7 0.029 0.090 0.7372 1 0.9070 254675115 18810 Plec 3 1 4 0 11 1 2 6 8 0.029 0.088 0.7343 1 0.9075 224809382 67771 Arpc5 0 0 0 0 0 0 0 1 0 0.029 0.042 0.6831 1 0.9193 9789943 56429 Dpt 1 1 1 1 1 1 1 0 1 0.029 0.042 0.6827 1 0.9193 239985513 108888 Atad3a 0 0 0 0 0 0 0 0 1 0.029 0.041 0.6823 1 0.9197 114205431 24015 Abce1 10 10 10 6 19 7 9 11 18 0.028 0.144 0.8263 1 0.8998 115496850 20740 Spna2 3 2 6 2 14 1 5 4 12 0.028 0.100 0.7521 1 0.9051 166064040 12824 Col2a1 0 0 0 0 0 0 0 0 1 0.028 0.038 0.6790 1 0.9210 226423871 13169 Dbnl 0 0 0 0 1 0 0 0 0 0.027 0.039 0.6806 1 0.9201 31560697 14958 H1f0 13 14 15 11 13 14 16 13 11 0.026 0.144 0.8252 1 0.8998 31980806 53328 Pgrmc1 4 6 5 2 7 4 6 4 6 0.026 0.084 0.7294 1 0.9081 34328471 56044 Rala 0 0 1 0 1 1 0 0 0 0.026 0.038 0.6796 1 0.9206 34610235 68585 Rtn4 0 0 1 1 0 0 0 0 0 0.026 0.038 0.6793 1 0.9206 6753364 12540 Cdc42 7 9 9 5 15 7 7 8 15 0.025 0.106 0.7612 1 0.9040 255003837 71169 Nbas 3 0 0 0 0 1 0 0 3 0.025 0.044 0.6851 1 0.9184 283436176 15381 Hnrnpc 0 1 1 0 2 0 2 0 0 0.025 0.040 0.6811 1 0.9201 208431820 106522 Pkdcc 0 0 0 1 0 0 0 0 0 0.024 0.037 0.6781 1 0.9210 94407692 382231 8030474K03Rik 0 0 0 0 1 0 0 0 0 0.024 0.035 0.6766 1 0.9219 6680047 14694 Gnb2l1 33 40 37 31 55 40 35 39 46 0.023 0.215 0.9865 1 0.8996 Diabetes Page 50 of 73

262050625 20832 Ssr4 16 22 20 15 20 19 18 20 20 0.023 0.164 0.8654 1 0.8988 148747518 12937 Pcdha6 0 0 1 0 0 0 0 0 0 0.023 0.032 0.6739 1 0.9228 9256519 56040 Rplp1 3 3 3 2 5 3 3 4 3 0.022 0.057 0.6980 1 0.9149 8567340 54160 Copg2 0 0 0 0 1 0 0 0 0 0.022 0.032 0.6742 1 0.9228 122114537 320528 Vps13c 0 0 0 0 1 0 0 0 0 0.022 0.031 0.6738 1 0.9228 9256628 18946 Pnliprp1 66 70 65 51 92 70 68 70 73 0.021 0.274 1 1 0.9057 160333869 18947 Pnliprp2 30 29 28 25 39 31 28 31 33 0.021 0.178 0.8975 1 0.8985 110625645 20660 Sorl1 0 0 0 0 0 0 0 1 0 0.021 0.030 0.6730 1 0.9233 46195798 13200 Ddost 17 19 19 18 32 18 21 23 25 0.020 0.144 0.8267 1 0.8998 124486727 78913 Ltn1 0 0 0 0 0 0 1 0 0 0.020 0.030 0.6730 1 0.9233 27370038 231279 Guf1 0 0 0 0 1 0 0 0 0 0.020 0.029 0.6722 1 0.9237 113205053 21429 Ubtf 0 0 0 0 1 0 0 0 0 0.020 0.029 0.6722 1 0.9237 312433955 11426 Macf1 1 0 0 0 0 0 0 0 0 0.020 0.028 0.6713 1 0.9242 126722649 15965 Ifna2 0 0 0 0 1 0 0 0 0 0.020 0.027 0.6707 1 0.9242 199559777 19060 Ppp5c 0 0 0 0 1 0 0 0 1 0.020 0.027 0.6707 1 0.9242 84043961 226982 Eif5b 6 7 10 4 15 6 4 11 13 0.019 0.084 0.7290 1 0.9084 13385932 67890 Ufm1 6 8 4 4 10 6 5 6 9 0.019 0.072 0.7142 1 0.9111 237681133 14109 Fau 3 3 3 3 4 3 3 3 4 0.019 0.052 0.6923 1 0.9164 113931156 69713 Pin4 0 0 0 1 1 0 0 1 1 0.019 0.027 0.6704 1 0.9247 6755206 19177 Psmb7 1 1 2 0 1 1 1 1 2 0.018 0.029 0.6718 1 0.9237 29244210 242291 Impad1 0 0 0 0 0 0 0 0 1 0.018 0.028 0.6714 1 0.9242 229608920 116847 Prelp 0 0 0 0 1 0 0 0 0 0.018 0.026 0.6697 1 0.9247 21312594 70456 Brp44 0 0 0 0 1 0 0 0 0 0.018 0.026 0.6694 1 0.9251 242247109 74914 Cylc2 0 0 0 0 1 0 0 0 0 0.018 0.026 0.6694 1 0.9251 119672912 27967 Cherp 0 0 0 0 0 1 0 0 0 0.018 0.024 0.6684 1 0.9256 AMYS_HUMAN 278 AMY1C 14 10 15 10 15 13 12 12 16 0.017 0.096 0.7463 1 0.9058 13928670 65114 Vps35 0 0 1 1 2 1 1 2 0 0.017 0.028 0.6710 1 0.9242 247269547 13528 Dtnb 0 0 0 0 0 0 0 0 1 0.017 0.025 0.6689 1 0.9251 33859532 13138 Dag1 0 0 0 0 0 0 0 0 1 0.017 0.024 0.6684 1 0.9256 47564084 407819 BC031181 0 1 0 0 0 1 1 0 0 0.017 0.024 0.6678 1 0.9256 110625902 108123 Napg 0 1 0 0 1 0 0 1 0 0.017 0.022 0.6665 1 0.9266 13195624 67273 Ndufa10 4 3 5 4 7 3 4 5 7 0.016 0.054 0.6940 1 0.9161 13195674 19346 Rab6a 0 0 1 0 0 0 0 1 0 0.016 0.023 0.6676 1 0.9256 30142697 347712 Pramel7 0 0 0 0 0 0 1 0 0 0.016 0.022 0.6666 1 0.9261 6755372 27050 Rps3 62 58 57 51 69 57 58 63 64 0.015 0.174 0.8872 1 0.8986 27369557 75619 Fastkd2 0 0 1 0 0 0 0 0 0 0.015 0.021 0.6662 1 0.9266 258613856 77485 Stk31 0 1 0 0 0 0 0 0 0 0.015 0.021 0.6660 1 0.9266 291575137 16673 Krt36 0 0 0 0 1 0 0 0 0 0.015 0.020 0.6654 1 0.9271 149251053 100047429 LOC100047429 4 8 8 4 18 5 6 12 11 0.014 0.060 0.7010 1 0.9138 6671565 11776 Ap3d1 0 0 0 0 2 0 0 0 2 0.014 0.022 0.6665 1 0.9266 377834273 381884 Slc6a16 0 0 0 0 1 0 0 0 0 0.014 0.021 0.6659 1 0.9266 71067352 14664 Slc6a9 0 0 0 0 1 0 0 0 0 0.014 0.020 0.6654 1 0.9271 153791169 208777 Sned1 0 0 0 0 1 0 0 0 0 0.014 0.020 0.6653 1 0.9271 118403314 170791 Rbm39 0 0 1 0 0 0 0 0 0 0.014 0.020 0.6650 1 0.9271 85701564 100044193 LOC100044193 0 0 0 0 0 0 0 0 1 0.014 0.019 0.6643 1 0.9276 31982186 17448 Mdh2 33 39 41 32 48 33 35 43 46 0.013 0.123 0.7878 1 0.9018 162138894 66590 Farsa 3 7 3 1 13 3 4 7 7 0.013 0.044 0.6843 1 0.9189 58037117 68349 Ndufs3 3 5 4 2 10 2 2 8 8 0.013 0.041 0.6820 1 0.9197 149263303 277089 Gm5068 0 1 0 0 2 0 0 0 2 0.013 0.021 0.6658 1 0.9266 6681179 13360 Dhcr7 1 0 1 2 1 0 0 1 2 0.013 0.020 0.6650 1 0.9271 143770878 69227 2810407C02Rik 0 0 0 0 1 0 0 0 0 0.013 0.019 0.6646 1 0.9276 50582589 442827 Rab44 0 0 0 0 0 0 0 0 1 0.013 0.019 0.6642 1 0.9276 83009766 637657 LOC637657 0 0 0 0 1 0 0 0 0 0.013 0.018 0.6636 1 0.9281 157277969 229279 Hnrnpa3 9 7 10 8 14 8 9 11 11 0.012 0.052 0.6921 1 0.9164 31982236 16403 Itga6 0 0 0 0 1 0 0 0 0 0.012 0.018 0.6636 1 0.9281 163659879 14806 Grik2 0 0 0 0 0 1 0 0 0 0.012 0.018 0.6634 1 0.9281 116812914 626578 Gbp10 0 0 0 1 0 0 0 0 0 0.012 0.018 0.6634 1 0.9281 6753406 12613 Cel 90 89 78 71 103 90 91 80 86 0.011 0.148 0.8329 1 0.8995 171184435 57874 Ptplad1 0 1 0 0 2 0 0 1 2 0.011 0.018 0.6634 1 0.9281 6754272 15874 Iapp 1 1 0 0 0 1 0 1 1 0.011 0.016 0.6621 1 0.9286 6677801 20068 Rps17 13 10 12 8 19 10 12 14 14 0.010 0.053 0.6934 1 0.9161 Page 51 of 73 Diabetes

30089677 110920 Hspa13 1 1 1 1 2 1 1 1 2 0.010 0.015 0.6619 1 0.9291 217035166 104799 Vipar 0 0 0 0 1 0 0 0 0 0.010 0.015 0.6617 1 0.9291 124486670 71803 Slc25a18 0 0 0 0 0 0 0 0 1 0.010 0.014 0.6611 1 0.9297 161760667 16905 Lmna 11 9 14 9 23 12 11 14 17 0.009 0.048 0.6885 1 0.9176 13385484 67126 Atp5e 4 4 5 3 5 4 4 5 4 0.009 0.028 0.6710 1 0.9242 226958458 237823 Pfas 0 0 0 0 2 0 0 0 2 0.009 0.016 0.6622 1 0.9286 40254507 67078 Pgp 1 0 0 0 1 0 0 0 0 0.009 0.013 0.6605 1 0.9297 76677922 232078 Thnsl2 0 0 0 0 0 0 0 1 1 0.009 0.013 0.6604 1 0.9297 21489955 97908 Hist1h3g 0 0 0 0 1 0 0 0 0 0.009 0.013 0.6602 1 0.9297 254028189 69878 Snrpf 0 0 0 0 0 0 1 0 0 0.009 0.013 0.6601 1 0.9302 110625879 228983 Osbpl2 0 0 1 0 0 0 0 0 0 0.009 0.012 0.6600 1 0.9302 33942089 233871 Atxn2l 0 0 0 0 1 0 0 0 1 0.009 0.012 0.6598 1 0.9302 160333212 12330 Canx 26 35 30 19 56 30 32 34 38 0.008 0.075 0.7185 1 0.9101 156713423 57296 Psmd8 1 0 1 0 2 1 2 0 1 0.008 0.013 0.6603 1 0.9297 21312562 70337 Iyd 0 0 0 0 1 0 0 0 0 0.008 0.012 0.6599 1 0.9302 119226241 20668 Sox13 0 1 0 0 0 0 0 0 0 0.008 0.012 0.6598 1 0.9302 13385680 67460 Decr1 1 8 5 3 8 2 3 9 6 0.007 0.022 0.6667 1 0.9261 160333372 17022 Lum 5 4 3 2 7 3 4 4 6 0.007 0.020 0.6651 1 0.9271 21312554 70257 2010107E04Rik 0 0 0 0 1 0 0 0 0 0.007 0.010 0.6588 1 0.9307 295424137 209318 Gps1 0 0 0 0 1 0 0 0 0 0.007 0.010 0.6587 1 0.9307 77736535 71116 Stx18 0 0 0 0 1 0 0 0 0 0.007 0.010 0.6585 1 0.9312 257196177 269401 Znf512b 0 0 0 0 0 0 0 0 1 0.007 0.010 0.6584 1 0.9312 215490074 20220 Sap18 0 0 0 0 1 0 0 0 1 0.007 0.009 0.6581 1 0.9312 112293264 14827 Pdia3 30 31 34 26 55 31 31 41 39 0.006 0.059 0.6994 1 0.9145 194018529 14852 Gspt1 8 7 7 5 12 8 4 8 11 0.006 0.025 0.6686 1 0.9251 7657031 50773 Nt5c 0 0 0 0 1 0 0 0 0 0.006 0.010 0.6582 1 0.9312 254553344 18642 Pfkm 0 1 1 0 0 0 0 0 0 0.006 0.009 0.6580 1 0.9312 31543694 20397 Sgpl1 0 0 0 0 1 0 0 0 0 0.006 0.009 0.6579 1 0.9312 6753488 26572 Cops3 0 0 1 0 0 0 0 0 1 0.006 0.009 0.6577 1 0.9318 255759989 21353 Tank 0 0 0 0 0 0 0 1 0 0.006 0.009 0.6576 1 0.9318 268839831 72361 Ces2g 0 0 0 0 0 0 0 1 0 0.006 0.008 0.6575 1 0.9318 6755973 22343 Lin7c 0 1 0 0 0 0 0 0 0 0.006 0.008 0.6574 1 0.9318 127138858 80718 Rab27b 0 0 0 0 1 0 0 0 0 0.006 0.008 0.6573 1 0.9318 7106303 13660 Ehd1 0 0 0 0 1 0 0 0 0 0.006 0.008 0.6572 1 0.9318 144922638 16709 Ktn1 0 0 0 0 0 0 0 0 1 0.006 0.008 0.6571 1 0.9318 30794386 72265 Tram1 12 15 14 10 26 14 13 16 19 0.005 0.030 0.6724 1 0.9237 23956156 67070 Lsm14a 0 0 0 0 0 0 1 0 0 0.005 0.008 0.6570 1 0.9318 347582617 20196 S100a13 0 0 0 0 1 0 0 0 0 0.005 0.007 0.6568 1 0.9323 21624635 103712 6330403K07Rik 0 0 0 0 0 0 0 0 1 0.005 0.007 0.6567 1 0.9323 22122795 235661 Dync1li1 0 0 0 0 0 0 0 1 0 0.005 0.006 0.6564 1 0.9323 33469051 72948 Tppp 0 0 0 0 1 0 0 0 0 0.005 0.006 0.6563 1 0.9323 13385492 67130 Ndufa6 1 2 3 1 4 3 0 2 3 0.004 0.009 0.6581 1 0.9312 21729749 18970 Polb 0 0 0 0 0 0 1 0 0 0.004 0.006 0.6561 1 0.9329 222831636 435528 Glyatl3 0 0 0 0 0 0 1 0 1 0.004 0.006 0.6561 1 0.9329 260166642 12387 Ctnnb1 0 0 0 0 1 0 0 0 0 0.004 0.006 0.6561 1 0.9329 58037329 73724 Mcee 0 0 0 0 1 0 0 0 0 0.004 0.005 0.6558 1 0.9329 84781779 230075 Ndufb6 0 0 0 0 0 0 0 1 0 0.004 0.005 0.6557 1 0.9329 254540041 67068 Dynlrb1 0 0 0 1 1 0 0 0 0 0.004 0.005 0.6556 1 0.9329 113680352 12408 Cbr1 7 6 6 5 12 7 7 6 9 0.003 0.013 0.6606 1 0.9297 13385890 67841 Atg3 0 0 0 0 1 0 0 0 0 0.003 0.005 0.6554 1 0.9334 6677759 19877 Rock1 0 0 0 0 1 0 0 0 0 0.003 0.004 0.6550 1 0.9334 85701762 214568 Gm136 0 0 0 0 1 0 0 0 0 0.003 0.004 0.6549 1 0.9334 77404392 56463 Snd1 113 125 127 92 175 116 107 138 145 0.002 0.041 0.6821 1 0.9197 13374559 109660 Ctrl 43 37 44 29 71 38 40 49 51 0.002 0.022 0.6665 1 0.9266 149254610 100039731 Gm10051 15 15 16 18 15 17 17 16 14 0.002 0.014 0.6610 1 0.9297 19527236 103694 Tmed4 2 0 0 1 5 0 3 1 3 0.002 0.004 0.6547 1 0.9334 45433560 16574 Kif5c 0 0 0 0 0 0 0 0 1 0.002 0.004 0.6547 1 0.9334 347582639 109359 Fam175b 0 0 0 0 1 0 0 0 0 0.002 0.003 0.6544 1 0.9340 31981890 12010 B2m 0 1 0 0 0 0 0 0 0 0.002 0.003 0.6542 1 0.9340 124487235 244879 Npat 0 0 0 0 0 0 0 0 1 0.002 0.003 0.6542 1 0.9340 124358932 207214 Larp4 0 0 0 1 0 0 0 1 1 0.002 0.002 0.6541 1 0.9340 Diabetes Page 52 of 73

156616286 245026 Col6a6 0 0 1 0 0 0 0 0 0 0.002 0.002 0.6540 1 0.9340 6753738 26905 Eif2s3x 8 11 12 10 8 8 6 11 15 0.001 0.007 0.6565 1 0.9323 31559970 68796 Tmem214 13 19 21 10 29 11 14 24 25 0.001 0.004 0.6548 1 0.9334 42476274 170750 Xpnpep1 0 0 0 0 1 0 0 0 0 0.001 0.002 0.6539 1 0.9345 6679641 13726 Emd 0 0 0 0 1 0 0 0 0 0.001 0.002 0.6537 1 0.9345 7242148 26908 Eif2s3y 0 0 0 0 1 0 0 0 0 0.001 0.001 0.6534 1 0.9345 93102417 353172 Gars 11 10 12 9 21 9 13 13 15 0.000 0.002 0.6538 1 0.9345 31980762 20656 Sod2 3 2 2 5 6 0 2 5 6 0.000 0.000 0.6530 1 0.9351 27229101 70564 5730469M10Rik 0 0 0 0 1 0 0 0 0 0.000 -0.001 0.6525 1 0.9357 167555029 14161 Fga 1 0 0 0 1 1 0 0 1 0.000 -0.001 0.6524 1 0.9357 9790015 56334 Tmed2 8 7 9 6 17 9 7 10 12 0.000 -0.002 0.6519 1 0.9357 83699424 19899 Rpl18 13 14 14 13 17 12 16 14 15 0.000 -0.002 0.6517 1 0.9362 21426889 27207 Rps11 23 23 24 21 28 22 25 24 25 0.000 -0.003 0.6511 1 0.9368 50053824 216238 Eea1 1 1 0 0 0 0 0 0 0 -0.001 -0.001 0.6523 1 0.9357 110227381 12336 Capns1 0 0 0 0 1 0 0 1 1 -0.001 -0.001 0.6521 1 0.9357 22094081 26397 Map2k3 0 0 1 0 0 0 0 0 0 -0.001 -0.002 0.6519 1 0.9357 71061455 74006 Dnm1l 0 0 0 0 1 0 0 1 0 -0.001 -0.002 0.6517 1 0.9362 309267099 640856 LOC640856 1 1 0 1 0 1 1 1 0 -0.002 -0.002 0.6517 1 0.9362 32567788 233489 Picalm 0 0 0 0 0 0 1 0 0 -0.002 -0.002 0.6516 1 0.9362 31982664 16434 Itpa 0 0 0 0 1 0 0 1 0 -0.002 -0.003 0.6515 1 0.9362 357197128 71810 Ranbp3 0 0 0 0 1 0 0 0 0 -0.002 -0.003 0.6514 1 0.9362 114052106 53607 Snrpa 0 1 0 0 2 1 0 2 0 -0.002 -0.003 0.6513 1 0.9362 85702095 434172 Gm5592 1 0 0 0 0 0 0 0 0 -0.002 -0.003 0.6512 1 0.9362 158854016 21402 Skp1a 0 0 0 0 1 0 0 0 0 -0.002 -0.003 0.6512 1 0.9362 10946854 19139 Prps1 0 0 0 0 1 0 0 0 0 -0.002 -0.003 0.6511 1 0.9368 21313588 52551 Sgta 0 0 0 0 1 0 0 0 0 -0.002 -0.003 0.6510 1 0.9368 78191777 208846 Daam1 0 0 1 0 0 0 0 1 0 -0.002 -0.003 0.6510 1 0.9368 261824055 14227 Fkbp2 5 6 7 8 11 5 6 6 12 -0.002 -0.009 0.6485 1 0.9392 109134362 53379 Hnrnpa2b1 10 13 15 16 23 11 12 19 20 -0.002 -0.011 0.6475 1 0.9398 209862989 22201 Uba1 5 18 13 8 35 10 11 16 26 -0.002 -0.014 0.6461 1 0.9416 21312500 109821 F11 0 0 0 0 1 0 0 0 0 -0.003 -0.004 0.6507 1 0.9368 84370314 381113 Cdkl4 0 0 0 1 0 0 0 0 0 -0.003 -0.005 0.6504 1 0.9374 22164768 67179 Ccdc25 0 0 0 0 1 0 0 0 0 -0.003 -0.005 0.6503 1 0.9374 188528712 381903 Alg8 0 0 0 0 1 0 0 0 0 -0.003 -0.005 0.6503 1 0.9374 22094119 360013 Myo18a 0 0 0 0 1 0 0 0 0 -0.003 -0.005 0.6503 1 0.9374 157041229 18521 Pcbp2 3 3 3 3 4 3 3 3 4 -0.003 -0.008 0.6490 1 0.9386 13385958 67941 Rps27l 11 11 15 11 14 10 11 13 15 -0.003 -0.014 0.6459 1 0.9416 31981100 20044 Rps14 10 11 12 11 17 11 11 15 12 -0.003 -0.016 0.6453 1 0.9422 19526848 67247 Mosc2 11 8 10 9 18 13 8 13 11 -0.003 -0.017 0.6449 1 0.9428 244790089 242594 1700024P16Rik 0 0 0 0 0 0 1 1 0 -0.004 -0.005 0.6503 1 0.9374 170784811 19704 Upf1 0 0 0 0 1 0 0 1 0 -0.004 -0.005 0.6501 1 0.9374 125628675 71538 Fbxo9 0 0 0 0 1 0 0 0 0 -0.004 -0.006 0.6500 1 0.9374 270132817 94242 Tinagl1 0 0 0 0 0 0 0 0 1 -0.004 -0.006 0.6500 1 0.9374 218083891 257664 Olfr773 0 0 0 0 0 0 0 1 0 -0.004 -0.006 0.6499 1 0.9374 261823936 67674 Trmt112 0 1 0 0 0 1 0 0 0 -0.004 -0.006 0.6497 1 0.9380 125628650 67163 Ccdc47 0 0 1 0 0 0 0 0 1 -0.004 -0.006 0.6496 1 0.9380 149273202 100042025 LOC100042025 21 26 30 16 34 23 24 23 31 -0.004 -0.031 0.6401 1 0.9499 40254350 66146 Tmem57 0 0 0 0 0 0 1 0 0 -0.005 -0.007 0.6494 1 0.9380 110735426 192897 Itgb4 0 0 0 1 0 0 0 0 0 -0.005 -0.007 0.6492 1 0.9386 6755763 21681 Alyref 1 0 0 0 0 0 0 0 0 -0.005 -0.008 0.6489 1 0.9386 239985468 72429 Dnajc25 1 0 0 0 0 0 0 0 0 -0.005 -0.008 0.6489 1 0.9386 124248577 23996 Psmc4 2 1 4 0 2 0 0 1 5 -0.005 -0.009 0.6483 1 0.9392 6753556 13033 Ctsd 11 8 12 9 11 9 9 10 13 -0.005 -0.022 0.6430 1 0.9454 6754976 18477 Prdx1 19 18 17 16 22 21 17 19 17 -0.005 -0.035 0.6392 1 0.9520 19482160 72042 Cotl1 0 0 0 0 1 0 1 1 1 -0.006 -0.008 0.6489 1 0.9386 15011843 20768 Sephs2 0 0 0 0 0 0 0 1 0 -0.006 -0.008 0.6489 1 0.9386 170650655 231549 Lrrc8d 0 1 0 0 0 0 0 0 0 -0.006 -0.008 0.6489 1 0.9386 30425032 105559 Mbnl2 0 0 0 1 0 0 0 0 0 -0.006 -0.009 0.6483 1 0.9392 148747198 27267 Cars 7 10 11 4 17 5 7 13 14 -0.006 -0.027 0.6415 1 0.9473 21313554 66286 Sec11c 13 18 13 12 15 12 15 15 14 -0.006 -0.030 0.6406 1 0.9493 6755376 20115 Rps7 22 24 26 21 34 25 25 24 27 -0.006 -0.047 0.6367 1 0.9583 Page 53 of 73 Diabetes

6677833 20194 S100a10 0 0 0 0 0 0 0 1 0 -0.007 -0.010 0.6480 1 0.9398 309267120 100505251 LOC100505251 0 0 1 1 0 0 0 0 0 -0.007 -0.010 0.6479 1 0.9398 176866126 94216 Col4a6 0 0 1 0 2 2 0 0 0 -0.007 -0.010 0.6477 1 0.9398 52486843 57752 Tacc2 0 1 0 0 0 0 0 0 0 -0.007 -0.011 0.6476 1 0.9398 17647119 66885 Acadsb 4 2 3 2 10 3 3 5 6 -0.007 -0.020 0.6437 1 0.9441 9910550 56529 Sec11a 5 5 6 4 7 5 4 7 5 -0.007 -0.024 0.6425 1 0.9460 30794476 19084 Prkar1a 0 0 1 0 0 1 0 0 1 -0.008 -0.011 0.6474 1 0.9398 283837907 216440 Os9 0 0 0 0 1 0 0 0 0 -0.008 -0.011 0.6473 1 0.9404 21703884 217666 L2hgdh 0 0 0 0 0 0 0 1 1 -0.008 -0.012 0.6472 1 0.9404 13385012 66449 Pam16 0 0 0 0 1 0 0 0 0 -0.008 -0.012 0.6470 1 0.9404 21703344 20224 Sar1a 4 6 10 5 9 8 7 6 6 -0.008 -0.035 0.6393 1 0.9513 255308899 27367 Rpl3 17 21 18 10 24 16 15 16 24 -0.008 -0.050 0.6364 1 0.9597 6753144 11984 Atp6v0c 0 0 0 0 1 0 0 1 1 -0.009 -0.012 0.6471 1 0.9404 109948275 18741 Pitx2 0 0 0 0 0 1 0 0 0 -0.009 -0.012 0.6468 1 0.9410 6679166 18295 Ogn 0 1 0 0 0 0 1 0 0 -0.009 -0.013 0.6467 1 0.9410 6755566 26941 Slc9a3r1 0 0 1 1 1 0 0 0 1 -0.009 -0.013 0.6467 1 0.9410 46909575 11692 Gfer 0 0 0 0 1 0 0 0 0 -0.009 -0.013 0.6466 1 0.9410 134288882 12819 Col15a1 0 0 0 0 1 0 0 0 0 -0.009 -0.013 0.6466 1 0.9410 28201978 27402 Pdhx 1 0 1 0 1 0 0 0 0 -0.009 -0.013 0.6464 1 0.9410 6755863 22027 Hsp90b1 74 78 70 53 113 69 75 74 89 -0.009 -0.118 0.6448 0.9814 1 19527174 101943 Sf3b3 0 0 0 0 1 0 0 0 0 -0.010 -0.014 0.6460 1 0.9416 124487439 207212 Arhgef17 0 0 0 0 0 1 0 0 0 -0.010 -0.014 0.6459 1 0.9416 188219567 17089 Lyar 0 0 0 0 1 0 1 0 0 -0.010 -0.014 0.6459 1 0.9416 161016826 13476 Reep5 13 18 16 9 23 14 18 15 15 -0.010 -0.061 0.6354 1 0.9664 165972309 20917 Suclg2 13 14 13 11 28 12 11 19 21 -0.010 -0.064 0.6353 1 0.9680 42415475 18453 P4hb 201 207 205 149 284 195 193 204 238 -0.010 -0.204 0.7011 0.9411 1 134288904 16443 Itsn1 0 0 0 0 0 0 0 0 1 -0.011 -0.014 0.6459 1 0.9416 52421794 72562 Pcbd2 0 0 0 0 1 0 0 1 0 -0.011 -0.016 0.6452 1 0.9422 160333502 11768 Ap1m2 1 0 1 0 1 0 0 0 0 -0.012 -0.016 0.6455 1 0.9422 167716839 5912286 COX1 0 0 0 0 1 0 0 0 1 -0.012 -0.016 0.6452 1 0.9422 23956272 107375 Slc25a45 1 0 0 0 0 0 0 0 1 -0.012 -0.017 0.6451 1 0.9428 31981822 13010 Cst3 0 0 0 1 1 0 0 0 0 -0.012 -0.017 0.6450 1 0.9428 269784764 234129 Tpte 0 0 0 0 0 0 0 1 0 -0.012 -0.018 0.6444 1 0.9435 82914650 622335 Gm6314 1 0 0 0 2 0 0 0 2 -0.012 -0.019 0.6441 1 0.9441 188497661 208104 Mlxip 3 2 2 2 1 4 2 0 0 -0.012 -0.025 0.6420 1 0.9467 23956222 74117 Actr3 1 2 1 1 5 1 2 0 4 -0.012 -0.026 0.6417 1 0.9473 31980648 11947 Atp5b 50 61 54 45 92 54 50 62 72 -0.012 -0.147 0.6583 0.9653 1 55742711 259300 Ehd2 0 0 0 0 1 0 0 1 0 -0.013 -0.019 0.6443 1 0.9435 28916693 227753 Gsn 2 0 2 3 6 0 2 4 4 -0.013 -0.031 0.6402 1 0.9499 21312570 70361 Lman1 17 18 18 20 33 13 20 26 25 -0.013 -0.093 0.6377 0.9984 0.9849 123701991 74213 Rbm26 0 0 0 0 1 0 0 0 0 -0.014 -0.019 0.6442 1 0.9435 356995917 13383 Dlg1 0 0 0 0 1 0 0 0 1 -0.014 -0.020 0.6436 1 0.9447 13384908 66322 1700011A15Rik 0 0 0 0 1 0 0 0 0 -0.014 -0.021 0.6435 1 0.9447 6677777 19941 Rpl26 22 23 20 19 21 22 23 19 19 -0.014 -0.098 0.6388 0.9948 0.9883 149251177 100040416 Gm10071 25 25 30 25 36 19 23 33 37 -0.014 -0.109 0.6420 0.9871 0.9961 12963511 20085 Rps19 33 34 30 23 35 27 31 30 33 -0.014 -0.113 0.6432 0.9846 0.9987 145301549 110257 Hba-a2 37 49 38 35 50 32 38 51 43 -0.014 -0.130 0.6499 0.9745 1 133922575 52653 Nudcd2 0 0 0 0 1 0 0 0 0 -0.015 -0.020 0.6436 1 0.9447 31981588 108664 Atp6v1h 0 0 0 0 1 0 1 0 0 -0.015 -0.021 0.6436 1 0.9447 25282409 68090 Yif1a 0 0 0 0 0 0 1 1 1 -0.015 -0.021 0.6434 1 0.9447 226958577 219158 2610301G19Rik 1 0 0 0 0 0 0 0 0 -0.015 -0.021 0.6434 1 0.9447 52345394 242894 Actr3b 1 1 0 1 1 0 0 0 0 -0.015 -0.022 0.6431 1 0.9454 134288917 13424 Dync1h1 4 5 7 1 38 3 7 9 24 -0.015 -0.068 0.6353 1 0.9695 219275596 70223 Nars 12 18 16 8 29 10 14 20 21 -0.015 -0.089 0.6371 1 0.9832 6754084 14862 Gstm1 20 23 28 14 27 19 20 22 27 -0.015 -0.105 0.6405 0.9896 0.9935 254553342 243168 Hsd17b13 21 27 28 21 38 25 26 25 31 -0.015 -0.117 0.6444 0.9822 1 7949137 110172 Slc35b1 0 0 0 0 0 0 0 0 1 -0.016 -0.023 0.6428 1 0.9454 160707921 11744 Anxa11 0 0 0 0 1 0 0 0 1 -0.016 -0.023 0.6428 1 0.9454 31982159 235043 Tmem205 0 0 0 0 1 0 0 0 0 -0.016 -0.023 0.6427 1 0.9460 145699110 258392 Olfr190 0 0 0 0 1 0 0 0 0 -0.016 -0.025 0.6422 1 0.9467 197313683 321022 Cdv3 3 2 5 2 7 4 3 5 3 -0.016 -0.047 0.6368 1 0.9583 Diabetes Page 54 of 73

13385090 110323 Cox6b1 14 18 13 11 18 15 16 16 11 -0.016 -0.098 0.6389 0.9940 0.9891 254281313 55946 Ap3m1 0 0 0 0 1 0 0 0 0 -0.017 -0.023 0.6429 1 0.9454 13385482 67125 Tspan31 0 0 0 0 1 0 0 0 0 -0.017 -0.023 0.6428 1 0.9454 149263552 100041649 Brp44l-ps 0 0 0 1 0 0 0 0 0 -0.017 -0.023 0.6427 1 0.9460 19527140 52163 Camk1 0 0 0 0 1 0 0 0 1 -0.017 -0.024 0.6425 1 0.9460 126090857 218236 Fam120a 0 0 0 0 1 0 0 0 0 -0.017 -0.024 0.6424 1 0.9460 163954941 14359 Fxr1 0 0 0 0 1 0 0 0 1 -0.017 -0.024 0.6424 1 0.9460 124249105 270120 Fat3 0 1 0 0 0 0 0 0 1 -0.017 -0.024 0.6423 1 0.9460 124378030 99412 Golga2 0 0 0 0 1 0 0 0 1 -0.017 -0.024 0.6423 1 0.9460 55741463 56612 Pfdn5 0 0 0 0 1 0 0 0 1 -0.017 -0.027 0.6413 1 0.9480 170650630 64383 Sirt2 0 0 0 0 1 0 0 0 0 -0.018 -0.025 0.6419 1 0.9467 86198335 66401 Nudt2 0 0 0 0 0 0 1 0 0 -0.018 -0.025 0.6419 1 0.9467 13386032 68051 Nutf2 1 1 0 0 1 1 0 0 0 -0.018 -0.026 0.6418 1 0.9473 10946928 59013 Hnrnph1 0 0 0 2 0 0 0 0 2 -0.018 -0.028 0.6410 1 0.9486 30794154 74111 Rbm19 0 0 0 0 1 0 0 0 0 -0.019 -0.025 0.6419 1 0.9467 124487380 18763 Pkd1 0 0 0 1 0 0 0 0 0 -0.019 -0.026 0.6418 1 0.9473 125625318 78912 Sp2 0 1 0 0 0 0 0 0 0 -0.019 -0.026 0.6416 1 0.9473 116256510 11771 Ap2a1 0 1 0 1 0 0 0 0 0 -0.019 -0.027 0.6414 1 0.9480 21312814 67724 Pop1 0 0 0 1 0 0 0 0 0 -0.019 -0.028 0.6410 1 0.9480 149250091 670832 Gm14059 20 21 21 16 21 18 19 19 22 -0.019 -0.126 0.6479 0.9775 1 255003735 19896 Rpl10a 19 21 21 18 32 19 18 25 24 -0.019 -0.132 0.6506 0.9737 1 10092608 14870 Gstp1 21 22 24 21 51 18 21 33 38 -0.019 -0.146 0.6578 0.9659 1 74271899 14677 Gnai1 0 0 0 1 0 0 1 1 1 -0.020 -0.026 0.6416 1 0.9473 7657329 50530 Mfap5 1 0 1 0 0 0 0 1 0 -0.020 -0.028 0.6410 1 0.9480 190684669 269587 Epb4.1 0 0 0 0 1 0 0 0 0 -0.020 -0.028 0.6410 1 0.9480 9506761 54342 Gnpnat1 0 0 1 0 0 0 0 1 1 -0.020 -0.029 0.6408 1 0.9486 85701644 67809 Fam82a2 0 0 0 0 0 0 0 0 1 -0.020 -0.029 0.6407 1 0.9486 27369676 211006 Sepsecs 0 1 0 0 1 0 0 0 0 -0.020 -0.029 0.6407 1 0.9486 40556286 230857 Ece1 1 0 0 0 1 0 1 0 1 -0.020 -0.030 0.6406 1 0.9493 28626508 19744 Rheb 0 0 2 0 1 0 0 2 0 -0.020 -0.032 0.6398 1 0.9506 170172524 13645 Egf 0 0 0 0 0 0 0 1 0 -0.021 -0.028 0.6412 1 0.9480 12963757 71780 Isyna1 0 0 0 1 1 0 0 0 0 -0.021 -0.029 0.6408 1 0.9486 22129041 258934 Olfr802 0 0 0 0 0 0 0 1 0 -0.021 -0.029 0.6407 1 0.9486 165972321 224640 Lemd2 0 0 0 0 1 0 0 0 0 -0.021 -0.030 0.6405 1 0.9493 9789881 56350 Arl3 0 1 0 0 1 0 0 0 0 -0.021 -0.030 0.6404 1 0.9493 149251501 100044829 LOC100044829 2 3 2 2 5 3 1 4 3 -0.021 -0.050 0.6364 1 0.9597 19527238 103711 Pnpo 0 0 0 0 0 1 0 0 0 -0.022 -0.029 0.6407 1 0.9486 122056578 12370 Casp8 0 0 0 0 0 0 1 0 0 -0.022 -0.030 0.6405 1 0.9493 31981027 56436 Adrm1 0 0 0 0 1 0 0 0 0 -0.022 -0.031 0.6402 1 0.9499 41235733 380840 Lyrm4 0 0 0 0 1 0 0 0 0 -0.022 -0.031 0.6401 1 0.9499 87159826 71302 Arhgap26 0 0 0 0 1 0 0 0 0 -0.022 -0.032 0.6399 1 0.9506 11230802 60595 Actn4 4 9 2 4 29 5 10 8 14 -0.022 -0.100 0.6393 0.9931 0.9900 111038118 15107 Hadh 13 18 12 9 19 10 13 15 17 -0.022 -0.126 0.6479 0.9767 1 163838641 11949 Atp5c1 15 21 20 11 37 17 19 25 21 -0.022 -0.152 0.6611 0.9633 1 28077029 74551 Pck2 20 30 26 20 47 21 23 30 39 -0.022 -0.172 0.6749 0.9534 1 33469123 27053 Asns 23 28 35 27 45 23 23 35 43 -0.022 -0.181 0.6811 0.9501 1 28077013 98366 Smap1 0 0 0 0 1 0 0 0 0 -0.023 -0.031 0.6402 1 0.9499 269973850 71865 Fbxo30 0 0 0 0 0 0 1 0 1 -0.023 -0.031 0.6402 1 0.9499 261862303 19339 Rab3a 0 0 0 0 0 1 1 0 0 -0.023 -0.031 0.6401 1 0.9499 247269408 53413 Exoc7 0 0 0 0 0 1 0 0 0 -0.023 -0.031 0.6401 1 0.9499 226693396 15366 Hmmr 0 1 0 0 0 0 0 0 0 -0.023 -0.032 0.6400 1 0.9499 12963579 66500 Slc30a7 0 0 1 0 1 0 0 0 1 -0.023 -0.032 0.6398 1 0.9506 21644577 68758 Abhd11 0 0 0 0 0 1 0 0 0 -0.023 -0.033 0.6398 1 0.9506 13384642 24071 Synj2bp 0 1 0 0 0 0 0 0 0 -0.023 -0.033 0.6396 1 0.9506 31560506 107765 Ankrd1 0 0 0 0 0 0 0 0 1 -0.023 -0.033 0.6396 1 0.9513 242397425 76138 Ccdc138 0 0 0 0 1 0 0 0 0 -0.023 -0.034 0.6394 1 0.9513 145207948 217069 Trim25 0 0 0 0 1 0 0 0 0 -0.023 -0.035 0.6392 1 0.9520 30725786 105847 Lmf2 0 0 0 0 2 1 2 1 0 -0.023 -0.036 0.6388 1 0.9527 126012517 13722 Aimp1 4 5 6 4 10 5 5 7 6 -0.023 -0.078 0.6358 1 0.9766 7106242 26358 Aldh1a7 3 3 4 3 20 5 5 4 12 -0.023 -0.087 0.6368 1 0.9815 11968166 64138 Ctsz 0 0 0 0 0 0 0 1 0 -0.024 -0.032 0.6398 1 0.9506 Page 55 of 73 Diabetes

6680710 11826 Aqp1 1 1 0 0 0 0 0 0 1 -0.024 -0.033 0.6396 1 0.9506 24418919 110078 Pygb 0 0 0 0 1 0 0 0 0 -0.024 -0.033 0.6396 1 0.9506 21313210 66958 Tmx2 0 0 0 0 1 0 0 0 0 -0.024 -0.034 0.6395 1 0.9513 25141335 70568 Cpne3 0 0 0 0 0 0 1 0 0 -0.024 -0.034 0.6395 1 0.9513 365777424 108737 Oxsr1 0 0 1 0 1 0 0 0 1 -0.024 -0.036 0.6390 1 0.9520 21450287 229663 Csde1 1 1 1 0 2 0 0 1 2 -0.024 -0.038 0.6384 1 0.9534 114326546 18648 Pgam1 5 8 10 5 15 8 7 8 11 -0.024 -0.099 0.6392 0.9931 0.9900 254553321 20091 Rps3a 48 40 45 44 64 44 36 52 56 -0.024 -0.244 0.7422 0.9297 1 95772123 17931 Ppp1r12a 0 0 0 1 0 0 0 0 0 -0.025 -0.034 0.6395 1 0.9513 8393173 53867 Col5a3 1 0 0 0 0 0 0 0 1 -0.025 -0.034 0.6394 1 0.9513 357588432 13043 Cttn 0 0 1 0 0 0 0 0 0 -0.025 -0.034 0.6393 1 0.9513 124486616 20286 Zc3h7b 1 0 0 0 0 0 0 0 0 -0.025 -0.036 0.6390 1 0.9520 7949055 53602 Hpcal1 0 0 0 0 0 0 0 0 1 -0.025 -0.036 0.6389 1 0.9520 21746165 73130 Tmed5 0 0 0 0 1 0 0 0 1 -0.025 -0.036 0.6388 1 0.9527 6678303 21780 Tfam 0 0 0 0 1 0 0 0 0 -0.025 -0.037 0.6387 1 0.9527 157951604 12331 Cap1 4 4 5 3 14 3 3 8 9 -0.025 -0.090 0.6373 1 0.9832 113679874 68312 Gstm7 0 0 1 0 0 0 0 0 1 -0.026 -0.035 0.6392 1 0.9520 6680878 12492 Scarb2 0 0 0 0 0 0 0 0 1 -0.026 -0.035 0.6391 1 0.9520 228480241 53375 Mtx2 0 0 0 0 0 0 0 0 1 -0.026 -0.035 0.6391 1 0.9520 6755364 20024 Sub1 0 0 0 0 1 0 0 0 0 -0.026 -0.036 0.6390 1 0.9520 6679337 18738 Pitpna 0 0 0 0 1 0 0 1 0 -0.026 -0.036 0.6389 1 0.9520 226874887 14923 Guk1 1 0 1 0 1 1 1 1 1 -0.026 -0.037 0.6386 1 0.9527 31543735 67760 Slc38a2 0 0 0 0 1 0 0 0 0 -0.026 -0.038 0.6385 1 0.9534 256818804 218333 BC018507 0 0 0 0 0 0 0 0 1 -0.027 -0.036 0.6389 1 0.9520 244789999 246221 Mpst 0 0 0 0 0 0 0 0 1 -0.027 -0.036 0.6389 1 0.9527 17647499 15130 Hbb-b2 0 0 0 0 1 0 0 0 0 -0.027 -0.037 0.6387 1 0.9527 31559918 230598 Nrd1 0 0 0 0 0 0 1 0 1 -0.027 -0.037 0.6387 1 0.9527 6678185 20935 Surf6 0 0 1 0 0 0 0 0 0 -0.027 -0.038 0.6385 1 0.9534 22094989 66525 Timm50 0 0 0 0 1 0 0 0 0 -0.027 -0.038 0.6384 1 0.9534 96975138 15452 Hprt 0 0 0 0 1 0 0 0 0 -0.027 -0.039 0.6383 1 0.9534 6678035 20604 Sst 0 0 1 0 1 0 0 0 0 -0.027 -0.039 0.6383 1 0.9534 34368584 69082 Zc3h15 0 1 0 0 0 0 0 0 1 -0.027 -0.039 0.6383 1 0.9540 158081796 14872 Gstt2 0 0 0 0 1 0 0 1 1 -0.027 -0.039 0.6382 1 0.9540 46359077 94187 Zfp423 0 0 0 0 0 0 0 1 0 -0.027 -0.039 0.6382 1 0.9540 155030209 319817 Rc3h2 1 0 0 0 0 0 0 0 0 -0.028 -0.037 0.6386 1 0.9527 293597551 56526 38961 0 0 0 1 0 0 0 0 0 -0.028 -0.037 0.6386 1 0.9527 31981592 98878 Ehd4 0 0 0 0 1 0 0 0 0 -0.028 -0.038 0.6385 1 0.9534 309263691 100043674 Gm9840 1 0 1 0 0 0 1 0 1 -0.028 -0.038 0.6384 1 0.9534 153792534 19386 Ranbp2 0 0 0 0 0 0 0 0 1 -0.028 -0.039 0.6383 1 0.9534 21311891 74122 Tmem43 0 0 0 0 1 0 0 0 0 -0.028 -0.039 0.6382 1 0.9540 58037467 76809 Bri3bp 0 0 0 0 1 0 0 0 0 -0.028 -0.040 0.6381 1 0.9540 254587947 110854 Ppp2r4 0 0 1 0 0 0 0 0 0 -0.028 -0.040 0.6380 1 0.9540 124286823 52335 Atxn1l 0 0 0 0 1 0 0 0 0 -0.028 -0.040 0.6379 1 0.9547 124487099 68693 Hnrnpul2 0 0 0 0 1 0 0 0 0 -0.028 -0.040 0.6379 1 0.9547 257196211 67775 Rtp4 0 0 0 0 1 0 0 0 0 -0.028 -0.041 0.6379 1 0.9547 13591862 56086 Set 0 1 1 0 2 2 1 1 1 -0.028 -0.041 0.6378 1 0.9547 27552760 28185 Tomm70a 0 0 0 0 0 0 1 0 0 -0.028 -0.041 0.6378 1 0.9547 31982724 18432 Mybbp1a 0 1 1 0 6 2 0 1 4 -0.028 -0.055 0.6358 1 0.9627 13384700 66073 Txndc12 0 0 0 0 1 0 0 0 0 -0.029 -0.040 0.6379 1 0.9547 6753374 12550 Cdh1 1 1 1 0 1 0 1 1 1 -0.029 -0.041 0.6379 1 0.9547 258613991 30050 Fbxw2 0 0 1 0 0 0 0 0 0 -0.029 -0.041 0.6378 1 0.9547 21703764 212442 Lactb2 0 0 0 0 1 0 0 1 1 -0.029 -0.041 0.6377 1 0.9554 170932536 13680 Ddx19a 0 0 1 0 0 0 0 0 0 -0.029 -0.041 0.6377 1 0.9554 270309140 108989 Tpr 1 0 0 0 0 0 0 0 0 -0.029 -0.041 0.6377 1 0.9554 31980808 53356 Eif3g 2 5 4 4 6 4 3 3 6 -0.029 -0.096 0.6385 0.9957 0.9874 146219837 13669 Eif3a 11 19 20 13 35 12 13 26 26 -0.029 -0.183 0.6832 0.9490 1 148747128 16430 Stt3a 23 28 28 24 30 22 28 23 30 -0.029 -0.207 0.7038 0.9403 1 161016833 13479 Dpep1 0 0 0 0 1 0 0 0 0 -0.030 -0.041 0.6379 1 0.9547 117959921 14683 Gnas 0 0 0 0 1 0 0 0 0 -0.030 -0.041 0.6378 1 0.9547 116063542 242721 Klhdc7a 0 0 1 0 0 0 0 0 0 -0.030 -0.043 0.6374 1 0.9561 208431789 107242 AI837181 0 0 0 0 1 0 0 0 0 -0.030 -0.044 0.6373 1 0.9561 Diabetes Page 56 of 73

7305247 17110 Lyz1 0 0 0 0 0 0 1 0 0 -0.030 -0.047 0.6368 1 0.9576 226958374 19027 Sypl 2 2 3 2 4 2 2 3 3 -0.030 -0.074 0.6355 1 0.9734 256000784 22003 Tpm1 4 3 4 2 2 2 3 3 4 -0.030 -0.075 0.6355 1 0.9742 159032014 227331 Gigyf2 0 0 0 0 1 0 0 0 0 -0.031 -0.042 0.6377 1 0.9554 126116585 16678 Krt1 1 0 0 0 0 0 0 0 0 -0.031 -0.042 0.6376 1 0.9554 51592076 14385 Slc37a4 0 0 1 0 0 0 0 1 0 -0.031 -0.042 0.6375 1 0.9554 149269959 546711 LOC546711 0 0 0 0 0 0 0 0 1 -0.031 -0.043 0.6374 1 0.9561 12963631 67180 Yipf5 0 0 0 0 0 0 0 0 1 -0.031 -0.046 0.6370 1 0.9576 8659568 16623 Klk1b1 0 0 0 0 1 0 0 0 1 -0.031 -0.046 0.6370 1 0.9576 124430539 67708 1810048J11Rik 0 0 0 0 1 0 0 0 0 -0.031 -0.047 0.6368 1 0.9583 83745120 67186 Rplp2 22 19 20 18 29 15 16 25 28 -0.031 -0.217 0.7140 0.9369 1 82617575 107508 Eprs 21 18 26 18 54 15 20 31 39 -0.031 -0.243 0.7419 0.9297 1 22095015 76893 Lass2 0 0 0 0 1 0 0 0 0 -0.032 -0.042 0.6376 1 0.9554 6753632 13350 Dgat1 0 0 1 0 1 0 0 1 0 -0.032 -0.043 0.6374 1 0.9561 17975504 67384 Bag4 0 0 0 0 0 0 0 1 0 -0.032 -0.045 0.6372 1 0.9569 261823961 17920 Myo6 0 0 0 0 1 0 0 0 0 -0.032 -0.045 0.6371 1 0.9569 6754870 18117 Cox4nb 0 0 1 0 0 0 0 0 0 -0.032 -0.045 0.6371 1 0.9569 124487299 228850 Ralgapb 0 0 0 0 0 0 1 0 0 -0.032 -0.046 0.6369 1 0.9576 124107623 70673 Prdm16 2 3 2 1 2 2 2 2 2 -0.032 -0.065 0.6353 1 0.9687 256220113 69634 Clybl 1 2 2 1 7 0 0 5 3 -0.032 -0.079 0.6358 1 0.9766 225579033 269951 Idh2 15 22 24 14 29 16 20 22 24 -0.032 -0.221 0.7181 0.9357 1 122937353 14255 Flt3 0 1 0 0 0 1 0 1 0 -0.033 -0.046 0.6369 1 0.9576 31981013 110265 Msra 0 0 1 0 1 0 1 0 0 -0.033 -0.046 0.6369 1 0.9576 287327708 208194 Exog 0 0 0 0 0 0 1 0 0 -0.033 -0.047 0.6368 1 0.9583 224994271 218503 Fcho2 1 0 1 0 0 1 0 0 0 -0.033 -0.049 0.6365 1 0.9590 226531119 16859 Lgals9 0 0 0 0 0 0 0 0 1 -0.033 -0.049 0.6365 1 0.9590 124249054 224170 Dzip3 0 0 0 0 2 0 0 2 1 -0.033 -0.052 0.6361 1 0.9612 7710096 20649 Sntb1 1 0 1 1 5 0 0 3 2 -0.033 -0.062 0.6354 1 0.9664 62945396 242505 Rasef 2 2 2 2 2 2 2 2 2 -0.033 -0.068 0.6353 1 0.9703 126723336 12034 Phb2 4 6 8 6 14 4 6 9 11 -0.033 -0.135 0.6522 0.9715 1 9903607 56530 Cnpy2 7 5 8 7 15 8 6 10 9 -0.033 -0.140 0.6549 0.9687 1 6680832 12314 Calm2 12 12 14 11 16 15 14 12 9 -0.033 -0.174 0.6763 0.9528 1 285026486 73103 3110009E18Rik 0 0 0 0 0 1 0 0 0 -0.034 -0.046 0.6370 1 0.9576 145207950 21887 Tle3 0 0 1 0 0 0 0 0 0 -0.034 -0.047 0.6368 1 0.9583 13384998 66437 Fis1 0 0 0 0 1 0 0 0 0 -0.034 -0.047 0.6368 1 0.9583 24418933 264895 Acsf2 0 0 0 0 0 0 1 0 0 -0.034 -0.048 0.6367 1 0.9583 20149756 192170 Eif4a3 0 0 0 0 1 0 0 0 0 -0.034 -0.048 0.6367 1 0.9583 150456419 13211 Dhx9 0 0 0 0 1 0 0 1 0 -0.034 -0.048 0.6366 1 0.9590 6681203 13405 Dmd 0 0 0 0 1 0 0 0 0 -0.034 -0.049 0.6365 1 0.9590 340745361 623198 Gm6408 0 0 0 0 1 0 0 0 0 -0.034 -0.049 0.6365 1 0.9590 7304971 26754 Cops5 1 0 1 0 1 0 0 0 1 -0.034 -0.049 0.6364 1 0.9597 111162655 102323 Dcun1d2 0 1 0 0 0 0 1 0 1 -0.034 -0.050 0.6363 1 0.9597 170295840 21849 Trim28 1 1 2 0 1 1 0 1 2 -0.034 -0.056 0.6357 1 0.9634 115334671 56752 Aldh9a1 11 11 13 6 15 9 8 11 15 -0.034 -0.173 0.6752 0.9534 1 254553337 19946 Rpl30 29 26 38 19 42 25 27 32 35 -0.034 -0.276 0.7823 0.9232 1 6677975 20462 Tra2b 0 0 0 0 1 0 0 0 0 -0.035 -0.048 0.6366 1 0.9583 254675249 17127 Smad3 0 1 0 0 0 0 0 0 0 -0.035 -0.048 0.6366 1 0.9590 224967102 67017 2010011I20Rik 0 0 0 0 1 0 0 0 0 -0.035 -0.049 0.6365 1 0.9590 10946822 58520 0610007P14Rik 0 0 0 0 1 0 0 0 0 -0.035 -0.049 0.6364 1 0.9597 153791768 77065 Ints7 0 0 1 0 0 0 0 0 0 -0.035 -0.052 0.6362 1 0.9605 29789343 27979 Eif3b 4 6 6 4 20 5 2 10 14 -0.035 -0.150 0.6603 0.9639 1 26892291 28113 Tinf2 0 0 0 0 0 0 0 1 0 -0.036 -0.049 0.6365 1 0.9590 90991708 330812 Rnf150 0 0 1 0 0 0 0 0 0 -0.036 -0.050 0.6363 1 0.9597 12025542 56495 Asna1 0 1 1 0 1 0 0 1 0 -0.036 -0.050 0.6363 1 0.9597 31981068 56615 Mgst1 1 0 1 1 1 0 0 0 0 -0.036 -0.051 0.6362 1 0.9605 6679765 14148 Fdx1 1 0 1 0 1 0 0 1 0 -0.036 -0.052 0.6361 1 0.9605 84662736 19988 Rpl6 29 29 28 27 42 27 27 32 34 -0.036 -0.305 0.8217 0.9194 1 34328234 20732 Spint1 0 0 0 0 1 0 0 0 0 -0.037 -0.049 0.6364 1 0.9597 37674242 69550 Bst2 0 0 0 0 1 0 0 0 0 -0.037 -0.050 0.6364 1 0.9597 110815859 13047 Cux1 0 0 0 0 1 1 0 0 1 -0.037 -0.051 0.6363 1 0.9605 269914154 239673 4732456N10Rik 0 0 0 0 0 0 0 1 1 -0.037 -0.053 0.6360 1 0.9612 Page 57 of 73 Diabetes

119226243 20384 Srsf5 1 0 0 0 1 0 0 0 0 -0.037 -0.055 0.6358 1 0.9627 67846099 30056 Timm9 0 0 1 0 1 0 0 1 1 -0.037 -0.056 0.6357 1 0.9627 158749640 50907 Preb 2 1 2 0 7 2 1 3 4 -0.037 -0.089 0.6371 1 0.9832 9789985 56357 Ivd 7 8 11 8 14 8 9 8 12 -0.037 -0.163 0.6683 0.9575 1 9790219 56431 Dstn 11 10 13 9 16 9 11 11 15 -0.037 -0.185 0.6845 0.9479 1 254675136 74978 Lrriq1 0 1 0 0 0 0 0 0 0 -0.038 -0.050 0.6364 1 0.9597 11096332 60315 Myg1 0 0 0 0 1 0 0 0 0 -0.038 -0.052 0.6361 1 0.9612 226958616 66375 Dhrs7 0 0 1 0 1 0 1 1 0 -0.038 -0.054 0.6359 1 0.9619 6754724 17463 Psmd7 0 1 1 0 1 1 1 1 0 -0.038 -0.056 0.6357 1 0.9634 31980629 22320 Vamp8 4 2 3 2 4 2 3 3 4 -0.038 -0.097 0.6387 0.9948 0.9883 7106439 22154 Tubb5 6 7 9 5 8 5 6 8 8 -0.038 -0.158 0.6651 0.9600 1 61557491 103266 AI597468 0 0 0 0 1 0 0 0 0 -0.039 -0.052 0.6361 1 0.9612 227116343 12491 Cd36 0 0 0 0 1 0 0 0 0 -0.039 -0.054 0.6359 1 0.9619 227908835 212933 Pm20d1 0 0 0 0 1 0 0 0 0 -0.039 -0.054 0.6359 1 0.9619 31982864 11983 Atpif1 0 1 0 0 0 0 0 0 0 -0.039 -0.057 0.6357 1 0.9634 45476573 16341 Eif3e 6 4 5 4 17 5 4 8 11 -0.039 -0.163 0.6687 0.9575 1 6680748 11946 Atp5a1 63 73 70 61 92 60 63 73 80 -0.039 -0.479 1 0.9229 1 62198210 67675 Cuta 0 0 0 0 1 0 0 0 0 -0.040 -0.053 0.6360 1 0.9612 254587918 18048 Klk1b4 0 0 0 0 0 0 0 1 0 -0.040 -0.056 0.6357 1 0.9634 266458391 16653 Kras 0 0 0 0 0 0 0 1 0 -0.040 -0.057 0.6356 1 0.9642 113205069 270166 Clpx 0 0 0 0 0 0 0 1 1 -0.040 -0.058 0.6356 1 0.9642 171543858 15356 Hmgcl 0 0 1 0 1 0 0 1 1 -0.040 -0.058 0.6356 1 0.9642 133778978 16004 Igf2r 0 0 0 0 0 0 0 0 1 -0.040 -0.058 0.6355 1 0.9649 51093840 223691 Eif3l 6 9 7 5 14 8 7 7 10 -0.040 -0.177 0.6781 0.9517 1 167716844 5912285 ND3 0 0 0 0 0 0 0 0 1 -0.041 -0.055 0.6358 1 0.9627 21704008 108735 Sft2d2 0 0 0 0 1 0 0 0 0 -0.041 -0.058 0.6356 1 0.9642 283945598 78428 Wibg 0 0 1 0 0 0 0 0 0 -0.041 -0.058 0.6356 1 0.9642 19482172 17252 Rdh11 0 0 0 0 0 0 0 1 1 -0.041 -0.059 0.6355 1 0.9649 113195686 16907 Lmnb2 1 0 1 0 0 0 0 0 1 -0.041 -0.059 0.6355 1 0.9649 9790049 56412 Noa1 0 0 1 0 0 0 0 0 0 -0.041 -0.059 0.6355 1 0.9649 85677506 26987 Eif4e2 0 0 0 0 1 0 0 0 0 -0.041 -0.060 0.6354 1 0.9657 148747526 19349 Rab7 14 9 9 11 20 10 10 15 13 -0.041 -0.214 0.7106 0.9377 1 18079339 11429 Aco2 27 32 36 25 60 28 27 39 44 -0.041 -0.369 0.9181 0.9164 1 112181302 227624 B230208H17Rik 0 0 0 0 0 0 0 0 1 -0.042 -0.055 0.6358 1 0.9627 167900448 212986 Scfd2 0 0 0 0 0 0 0 1 0 -0.042 -0.057 0.6357 1 0.9634 146219830 12388 Ctnnd1 0 0 0 0 1 0 0 0 0 -0.042 -0.057 0.6356 1 0.9642 10946850 17346 Mknk1 0 0 0 0 1 0 0 1 1 -0.042 -0.057 0.6356 1 0.9642 20806109 11545 Parp1 0 0 0 0 1 0 0 0 0 -0.042 -0.058 0.6356 1 0.9642 67846113 20637 Snrnp70 0 0 1 0 1 0 0 0 0 -0.042 -0.058 0.6356 1 0.9642 34328501 69083 Sult1c2 0 0 0 0 1 0 1 1 0 -0.042 -0.058 0.6355 1 0.9642 149263574 627375 Gm6750 0 0 0 0 0 1 1 0 0 -0.042 -0.060 0.6355 1 0.9657 226958501 74682 Wdr35 0 0 0 0 0 0 0 0 1 -0.042 -0.060 0.6354 1 0.9657 32401469 75050 Kif27 0 0 0 0 0 0 1 0 0 -0.042 -0.062 0.6354 1 0.9664 6679439 268373 Ppia 28 33 31 28 40 25 27 33 38 -0.042 -0.369 0.9183 0.9164 1 124486873 268857 Nlrc3 0 0 0 0 0 0 0 1 0 -0.043 -0.057 0.6356 1 0.9634 7304953 12504 Cd4 0 0 0 0 1 0 0 1 0 -0.043 -0.060 0.6355 1 0.9657 30424876 76187 Adhfe1 0 0 0 0 0 0 0 1 0 -0.043 -0.062 0.6354 1 0.9664 226342951 69683 2310044H10Rik 0 0 0 0 1 0 0 0 0 -0.043 -0.063 0.6353 1 0.9672 158854020 52665 Echdc1 0 0 0 0 0 0 0 1 1 -0.043 -0.063 0.6353 1 0.9672 158508568 19247 Ptpn11 0 0 0 0 1 0 0 0 0 -0.043 -0.064 0.6353 1 0.9680 116292744 268379 Abca13 0 0 0 0 0 0 0 0 1 -0.044 -0.060 0.6354 1 0.9657 13386046 68066 Slc25a39 0 0 0 0 1 0 0 1 0 -0.044 -0.060 0.6354 1 0.9657 112181198 18578 Pde4b 0 0 0 0 1 0 0 0 0 -0.044 -0.062 0.6354 1 0.9664 7305285 17748 Mt1 2 4 3 2 2 4 0 3 2 -0.044 -0.108 0.6414 0.9880 0.9952 13591860 54473 Tollip 0 0 0 0 1 0 0 0 0 -0.045 -0.058 0.6356 1 0.9642 189458807 70737 Cgn 0 0 0 0 0 0 0 1 0 -0.045 -0.065 0.6353 1 0.9687 124001582 338366 Mia3 0 2 1 0 5 1 1 3 3 -0.045 -0.095 0.6383 0.9966 0.9866 6754696 17319 Mif 3 6 3 1 8 3 4 4 5 -0.045 -0.135 0.6519 0.9723 1 29244556 331026 Gmppb 6 6 7 6 12 8 6 6 9 -0.045 -0.181 0.6813 0.9501 1 254540166 14828 Hspa5 144 147 147 124 186 131 134 148 156 -0.045 -0.857 1 0.9711 1 124517663 16952 Anxa1 0 0 0 0 1 0 0 0 0 -0.046 -0.064 0.6353 1 0.9680 Diabetes Page 58 of 73

116517290 26431 Git2 0 0 0 0 0 0 0 0 1 -0.046 -0.064 0.6353 1 0.9680 6679567 19285 Ptrf 0 0 1 0 1 0 1 0 1 -0.046 -0.065 0.6353 1 0.9680 91064872 244233 Cd163l1 0 0 0 0 0 1 0 0 0 -0.046 -0.065 0.6353 1 0.9687 110347529 74164 Nfx1 0 0 0 1 0 0 0 0 0 -0.046 -0.066 0.6353 1 0.9687 7305443 27176 Rpl7a 24 22 21 26 31 18 27 28 23 -0.046 -0.352 0.8921 0.9165 1 12963555 52633 Nit2 0 0 1 0 0 0 0 1 0 -0.047 -0.064 0.6353 1 0.9680 27369922 103967 Dnm3 1 1 0 0 0 1 0 1 0 -0.047 -0.065 0.6353 1 0.9687 283436077 244548 Elmod2 0 0 0 0 0 1 0 1 1 -0.047 -0.069 0.6353 1 0.9703 170650597 68303 Fam114a1 0 0 0 0 1 0 0 0 1 -0.048 -0.065 0.6353 1 0.9687 188528620 17764 Mtf1 0 0 0 0 1 0 0 0 0 -0.048 -0.068 0.6353 1 0.9695 153792001 19385 Ranbp1 0 1 0 0 0 1 1 0 0 -0.048 -0.071 0.6353 1 0.9719 153791358 81898 Sf3b1 0 0 0 0 1 0 0 0 0 -0.049 -0.073 0.6354 1 0.9734 18250288 28106 D17Wsu104e 3 3 3 4 5 1 3 5 5 -0.049 -0.126 0.6479 0.9767 1 6755963 22333 Vdac1 7 10 9 5 15 7 9 9 10 -0.049 -0.214 0.7103 0.9381 1 358439483 76614 Immt 12 11 16 12 21 12 10 13 20 -0.049 -0.264 0.7670 0.9253 1 188497650 109154 Mlec 16 19 18 15 22 15 16 19 19 -0.049 -0.301 0.8157 0.9198 1 6755152 19072 Prep 0 0 0 0 1 0 0 0 0 -0.050 -0.070 0.6353 1 0.9711 163954948 16549 Khsrp 0 0 0 0 1 0 0 0 0 -0.050 -0.071 0.6353 1 0.9719 88853581 14030 Ewsr1 0 0 0 0 1 0 0 0 0 -0.050 -0.073 0.6354 1 0.9726 194688157 14918 Gucy2d 0 0 0 0 1 0 0 0 0 -0.050 -0.073 0.6354 1 0.9726 145046267 20190 Ryr1 0 0 0 0 0 0 1 0 0 -0.050 -0.073 0.6354 1 0.9726 153945866 224902 Safb2 0 0 0 0 1 0 0 0 0 -0.050 -0.074 0.6354 1 0.9734 167716847 5912275 ND5 0 0 0 0 1 0 0 0 1 -0.051 -0.069 0.6353 1 0.9703 240255651 16202 Ilk 0 0 0 0 1 1 1 1 0 -0.051 -0.069 0.6353 1 0.9711 170295825 53419 Corin 0 0 0 0 1 0 0 0 0 -0.051 -0.070 0.6353 1 0.9711 21426823 80838 Hist1h1a 0 0 1 0 1 0 0 0 0 -0.051 -0.072 0.6354 1 0.9726 27754007 70316 Ndufab1 0 2 0 0 4 0 2 2 2 -0.051 -0.102 0.6399 0.9914 0.9917 83715998 11958 Atp5k 6 5 6 4 8 5 5 6 6 -0.051 -0.176 0.6780 0.9517 1 226958349 21991 Tpi1 17 12 19 14 25 15 16 15 19 -0.051 -0.305 0.8220 0.9194 1 13384784 66177 Ubl5 0 0 0 0 0 1 0 0 0 -0.052 -0.067 0.6353 1 0.9695 31981178 59007 Ngly1 0 0 0 0 1 0 0 0 0 -0.052 -0.075 0.6355 1 0.9742 37694070 94246 Arid4b 0 0 0 0 1 0 0 0 0 -0.052 -0.075 0.6355 1 0.9742 90568038 11303 Abca1 0 0 0 0 1 0 0 0 0 -0.052 -0.077 0.6356 1 0.9750 254281204 58865 Tdh 0 0 0 0 1 0 0 0 0 -0.053 -0.072 0.6354 1 0.9726 282721029 13017 Ctbp2 1 0 0 0 1 0 0 0 1 -0.053 -0.076 0.6356 1 0.9750 9789991 56348 Hsd17b12 1 1 1 1 5 1 2 1 3 -0.053 -0.103 0.6402 0.9905 0.9926 189409138 71902 Cand1 1 3 3 0 6 2 3 4 2 -0.053 -0.130 0.6500 0.9745 1 167716843 5912280 COX3 1 1 0 0 1 1 0 1 1 -0.054 -0.073 0.6354 1 0.9726 295317325 20619 Snap23 0 0 0 0 1 0 0 0 1 -0.054 -0.075 0.6355 1 0.9742 124248566 94109 Csmd1 0 0 1 0 0 0 0 0 0 -0.054 -0.077 0.6356 1 0.9750 269784743 211134 Lzts1 0 0 0 1 0 0 0 0 0 -0.054 -0.080 0.6360 1 0.9774 61888838 15108 Hsd17b10 4 4 5 2 18 3 3 8 12 -0.054 -0.196 0.6943 0.9439 1 240120117 26912 Gcat 29 33 36 29 47 28 27 36 40 -0.054 -0.449 1 0.9201 1 254939685 328108 Fam179b 0 1 0 0 0 0 0 0 0 -0.055 -0.073 0.6354 1 0.9734 31560712 12988 Csk 0 0 1 0 0 0 0 0 1 -0.055 -0.081 0.6360 1 0.9783 165932375 66870 Serbp1 4 6 8 6 16 5 6 7 12 -0.055 -0.218 0.7142 0.9369 1 21313278 76737 Creld2 6 6 7 5 19 7 5 9 12 -0.055 -0.238 0.7353 0.9310 1 146134409 67880 Dcxr 1 0 1 0 1 1 0 1 0 -0.056 -0.076 0.6356 1 0.9750 257196183 67959 Puf60 0 0 0 0 1 0 0 0 0 -0.056 -0.076 0.6356 1 0.9750 149254145 100042335 Rps15a-ps5 0 0 0 0 1 0 0 0 0 -0.056 -0.081 0.6360 1 0.9774 309271610 100039794 Gm2427 0 0 0 0 0 1 0 0 0 -0.056 -0.083 0.6363 1 0.9791 30023855 223527 Eny2 0 0 0 0 0 0 0 1 0 -0.056 -0.084 0.6364 1 0.9799 27754144 66046 Ndufb5 1 1 2 1 3 2 0 1 2 -0.056 -0.097 0.6386 0.9948 0.9883 6679891 14376 Ganab 4 6 6 2 13 5 5 6 7 -0.056 -0.197 0.6950 0.9435 1 22164798 20341 Selenbp1 6 4 9 5 15 7 5 7 11 -0.056 -0.225 0.7222 0.9345 1 14149647 20005 Rpl9 15 18 16 11 28 13 16 17 21 -0.056 -0.330 0.8573 0.9175 1 6680724 11845 Arf6 0 0 0 0 1 0 0 0 1 -0.057 -0.081 0.6360 1 0.9783 21426821 54127 Rps28 16 12 16 15 15 13 11 14 18 -0.057 -0.327 0.8535 0.9176 1 293597567 11674 Aldoa 17 21 21 18 23 19 17 17 23 -0.057 -0.372 0.9240 0.9164 1 158937258 77254 Yif1b 0 1 0 0 0 0 0 0 0 -0.058 -0.079 0.6358 1 0.9766 377837099 625473 Gm6590 0 0 0 0 0 0 1 0 0 -0.058 -0.080 0.6359 1 0.9774 Page 59 of 73 Diabetes

14141185 12638 Cftr 0 0 0 0 1 0 0 0 0 -0.058 -0.081 0.6360 1 0.9783 244791232 433771 Minos1 1 0 1 1 0 0 1 1 1 -0.058 -0.085 0.6365 1 0.9799 9789937 56445 Dnaja2 1 2 2 1 2 0 2 2 1 -0.058 -0.107 0.6411 0.9888 0.9943 254588014 66841 Etfdh 5 5 4 3 10 5 5 5 6 -0.058 -0.201 0.6984 0.9421 1 160358785 11480 Acvr2a 0 0 0 0 0 0 0 0 1 -0.059 -0.080 0.6359 1 0.9774 27229021 66925 Sdhd 1 0 0 0 0 0 0 0 0 -0.059 -0.083 0.6363 1 0.9791 21704156 109624 Cald1 1 0 1 0 0 0 0 0 0 -0.059 -0.083 0.6363 1 0.9791 68226431 319190 Hist2h2be 0 1 1 0 1 0 0 1 1 -0.059 -0.083 0.6363 1 0.9791 31560110 69237 Gtpbp4 0 0 0 0 1 0 0 0 0 -0.059 -0.083 0.6363 1 0.9799 237874259 14423 Galnt1 0 0 0 0 1 0 0 1 0 -0.059 -0.090 0.6373 0.9993 0.9840 160298199 14675 Gna14 0 0 0 0 1 0 0 0 0 -0.060 -0.084 0.6363 1 0.9799 14140240 66629 Golph3 0 0 0 0 1 0 0 0 0 -0.060 -0.085 0.6364 1 0.9799 21312712 67923 Tceb1 0 0 1 0 1 0 1 0 1 -0.060 -0.086 0.6366 1 0.9807 169234776 268822 Adck5 0 0 0 0 0 0 0 1 0 -0.060 -0.089 0.6371 1 0.9832 229094709 21399 Tcea1 1 0 0 0 1 0 0 0 0 -0.060 -0.089 0.6371 1 0.9832 227908837 111175 Pecr 0 0 0 0 0 0 0 1 0 -0.060 -0.090 0.6372 1 0.9832 29789289 93747 Echs1 12 11 11 15 17 8 10 15 17 -0.060 -0.313 0.8327 0.9186 1 157168326 192113 Atp12a 0 0 0 0 0 0 0 0 1 -0.061 -0.086 0.6367 1 0.9815 226246650 65962 Slc9a3r2 0 0 0 0 1 0 0 0 0 -0.061 -0.087 0.6368 1 0.9815 148229140 99371 Arfgef2 0 0 0 0 1 0 0 0 0 -0.061 -0.088 0.6369 1 0.9824 10946680 14264 Fmod 0 0 0 0 0 0 0 0 1 -0.061 -0.092 0.6376 0.9984 0.9849 23346561 98956 Nat10 0 0 0 0 1 0 0 0 0 -0.062 -0.083 0.6363 1 0.9791 149255960 435927 Gm5724 0 0 1 0 0 0 0 0 0 -0.062 -0.086 0.6366 1 0.9807 13385290 52502 Carhsp1 0 0 1 0 1 0 0 0 1 -0.062 -0.090 0.6373 0.9993 0.9840 117606368 18175 Nrap 0 0 0 0 0 0 0 0 1 -0.062 -0.091 0.6375 0.9984 0.9849 162287212 18109 Mycn 1 0 0 0 0 1 0 1 0 -0.062 -0.092 0.6376 0.9984 0.9849 115583687 192159 Prpf8 0 0 0 0 1 0 0 0 0 -0.062 -0.093 0.6377 0.9984 0.9849 21450345 234959 Med17 0 0 0 0 0 0 0 1 0 -0.063 -0.085 0.6365 1 0.9807 160837788 11867 Arpc1b 0 0 0 1 1 0 0 0 0 -0.063 -0.087 0.6368 1 0.9815 37537522 223650 Eppk1 0 0 0 0 1 1 1 1 1 -0.063 -0.089 0.6371 1 0.9832 161353449 67039 Rbm25 0 0 0 0 0 1 0 0 0 -0.063 -0.093 0.6378 0.9975 0.9857 171460960 76491 Abhd14b 6 5 8 5 5 5 5 5 7 -0.063 -0.226 0.7230 0.9342 1 15277331 66120 Fkbp11 15 19 17 13 29 15 17 17 21 -0.063 -0.414 0.9913 0.9176 1 255003752 224630 Bnip1 0 0 0 0 1 0 0 0 0 -0.064 -0.087 0.6368 1 0.9815 254675217 228545 Vps18 0 0 0 0 0 0 0 0 1 -0.064 -0.095 0.6382 0.9966 0.9866 119508441 67151 Psmd9 0 0 0 0 1 0 0 0 0 -0.064 -0.096 0.6385 0.9957 0.9874 309263479 100043217 Gm10237 0 0 0 0 0 0 1 0 0 -0.064 -0.097 0.6386 0.9948 0.9883 224809559 98415 Nucks1 0 1 1 0 0 0 0 1 1 -0.064 -0.097 0.6387 0.9948 0.9883 158937329 69605 Lnp 3 3 0 1 0 4 1 1 0 -0.064 -0.119 0.6453 0.9806 1 19526463 67397 Erp29 2 5 4 5 14 4 2 8 9 -0.064 -0.231 0.7277 0.9331 1 6755448 20333 Sec22b 7 7 11 6 13 5 6 9 13 -0.064 -0.265 0.7680 0.9250 1 34328230 11637 Ak2 9 10 14 9 17 10 7 14 14 -0.064 -0.310 0.8288 0.9189 1 42734487 52864 Slx4 0 0 0 1 0 0 0 0 0 -0.065 -0.089 0.6370 1 0.9824 12746442 65967 Eefsec 0 0 1 0 0 0 0 0 0 -0.065 -0.089 0.6370 1 0.9824 34328485 17025 Alad 0 0 0 0 1 0 0 0 0 -0.065 -0.089 0.6371 1 0.9832 13277394 17713 Grpel1 0 1 0 0 0 1 0 0 0 -0.065 -0.092 0.6376 0.9984 0.9849 9845273 56462 Mtch1 0 0 0 0 1 0 0 0 0 -0.065 -0.093 0.6379 0.9975 0.9857 13384930 66357 Ostc 2 2 3 2 3 2 2 2 3 -0.065 -0.146 0.6579 0.9659 1 31982520 11363 Acadl 3 4 4 1 8 2 1 7 5 -0.065 -0.174 0.6765 0.9523 1 21728372 66248 Alg5 2 2 4 0 8 2 3 3 5 -0.066 -0.187 0.6866 0.9474 1 6679261 18597 Pdha1 7 6 5 3 14 5 5 7 10 -0.066 -0.254 0.7548 0.9274 1 70778976 18655 Pgk1 19 21 22 19 31 18 21 20 24 -0.066 -0.448 1 0.9201 1 165377065 66588 Cmpk1 5 5 7 7 9 6 5 6 8 -0.067 -0.262 0.7638 0.9258 1 13385044 66489 Rpl35 7 7 7 6 9 5 7 7 8 -0.067 -0.277 0.7832 0.9230 1 161016799 11746 Anxa4 7 5 11 5 12 7 5 8 9 -0.067 -0.281 0.7882 0.9226 1 86198316 12304 Pdia4 39 41 49 30 57 36 37 43 49 -0.067 -0.637 1 0.9437 1 6755202 26446 Psmb3 0 0 0 0 1 0 0 0 1 -0.068 -0.094 0.6380 0.9966 0.9866 228008367 53320 Folh1 0 0 0 0 0 0 1 0 0 -0.068 -0.102 0.6398 0.9922 0.9909 6677805 20102 Rps4x 40 40 39 37 54 38 35 41 43 -0.068 -0.699 1 0.9523 1 31981382 23918 Impdh2 0 0 0 1 0 0 0 0 0 -0.069 -0.093 0.6379 0.9975 0.9857 6756053 22687 Zfp259 1 0 0 0 0 0 0 0 0 -0.069 -0.099 0.6391 0.9940 0.9891 Diabetes Page 60 of 73

13385006 66445 Cyc1 1 3 3 3 9 2 2 4 6 -0.069 -0.189 0.6880 0.9464 1 31543845 27368 Tbl2 1 4 3 3 10 2 2 6 6 -0.069 -0.201 0.6985 0.9421 1 21312816 67726 Fam114a2 0 0 0 0 1 0 0 0 0 -0.070 -0.096 0.6383 0.9957 0.9874 6679441 19038 Ppic 0 0 0 0 1 0 0 0 0 -0.070 -0.098 0.6388 0.9948 0.9883 46447825 75785 Klhl24 0 0 0 0 0 0 0 0 1 -0.070 -0.099 0.6391 0.9940 0.9891 112421031 19123 Proc 3 2 2 1 4 2 0 3 3 -0.070 -0.145 0.6575 0.9666 1 7948999 53381 Prdx4 12 12 13 9 21 11 10 14 15 -0.070 -0.373 0.9249 0.9164 1 8393853 53893 Nudt5 1 0 1 0 0 0 0 0 0 -0.071 -0.096 0.6385 0.9957 0.9874 110611222 56422 Hbs1l 0 0 0 0 1 0 0 0 0 -0.071 -0.100 0.6393 0.9931 0.9900 51712358 434050 Gm5576 0 0 0 0 0 1 0 0 0 -0.071 -0.101 0.6396 0.9922 0.9909 258613873 56369 Apip 0 0 0 0 1 0 0 0 0 -0.071 -0.103 0.6400 0.9914 0.9917 14916479 17113 M6pr 0 0 0 0 1 0 0 0 0 -0.072 -0.097 0.6387 0.9948 0.9883 167466243 83814 Nedd4l 0 0 0 0 0 0 1 0 0 -0.072 -0.099 0.6391 0.9940 0.9891 31982063 70266 Ccbl1 0 0 0 0 1 0 0 0 0 -0.072 -0.100 0.6394 0.9931 0.9900 111607430 16201 Ilf3 0 0 0 0 1 0 0 0 0 -0.072 -0.101 0.6396 0.9922 0.9909 21717751 171251 Vmn1r205 0 0 0 0 1 0 0 0 0 -0.072 -0.104 0.6404 0.9905 0.9926 23346461 226646 Ndufs2 1 1 1 2 3 2 1 1 2 -0.072 -0.135 0.6523 0.9715 1 110625719 68917 Hint2 0 1 1 0 4 0 0 3 0 -0.072 -0.136 0.6527 0.9715 1 33563266 17992 Ndufa4 9 8 10 9 10 9 8 8 9 -0.072 -0.324 0.8490 0.9178 1 37674236 69060 Pnlip 73 84 84 61 136 73 74 80 99 -0.072 -0.953 1 0.9798 1 171543869 15441 Hp1bp3 0 0 0 0 0 0 0 0 1 -0.073 -0.101 0.6397 0.9922 0.9909 39930599 72145 Wdfy3 1 0 0 0 0 0 0 0 0 -0.073 -0.108 0.6415 0.9880 0.9952 9845265 22186 Uba52 1 1 1 1 1 1 1 1 1 -0.073 -0.108 0.6415 0.9880 0.9952 6755995 22388 Wdr1 3 2 3 0 3 0 2 4 2 -0.073 -0.154 0.6628 0.9619 1 160333553 269261 Rpl12 18 18 22 21 26 16 17 22 23 -0.073 -0.474 1 0.9225 1 6753492 12721 Coro1a 0 0 0 0 1 0 0 0 0 -0.074 -0.100 0.6393 0.9931 0.9900 13384752 66140 Fam33a 0 0 0 0 0 1 0 0 0 -0.074 -0.103 0.6402 0.9905 0.9926 26006861 216134 Pdxk 0 0 1 0 1 0 0 0 1 -0.074 -0.104 0.6404 0.9905 0.9926 254588006 74354 Lrguk 0 0 0 0 0 0 0 0 1 -0.074 -0.105 0.6405 0.9896 0.9935 167716846 5912276 ND4 0 0 1 0 0 0 0 0 0 -0.074 -0.110 0.6420 0.9871 0.9961 21704100 231086 Hadhb 5 7 10 4 10 5 7 5 10 -0.074 -0.287 0.7969 0.9216 1 23956246 114679 Selm 0 0 0 0 1 0 0 0 0 -0.075 -0.105 0.6406 0.9896 0.9935 120300944 16553 Kif13a 0 0 0 0 1 0 0 0 0 -0.075 -0.106 0.6408 0.9896 0.9935 6678349 21843 Tial1 0 0 0 0 1 0 0 0 0 -0.075 -0.108 0.6416 0.9880 0.9952 46559406 224105 Pak2 0 0 1 0 0 0 0 0 0 -0.075 -0.112 0.6429 0.9855 0.9978 6755662 27058 Srp9 2 1 5 3 4 2 2 4 3 -0.075 -0.182 0.6824 0.9495 1 124378056 100034363 Tmsb15b2 0 0 0 1 0 0 0 0 0 -0.076 -0.106 0.6409 0.9888 0.9943 161016790 11987 Slc7a1 1 1 1 0 0 0 0 0 0 -0.076 -0.112 0.6429 0.9855 0.9978 309270053 544973 Gm10257 0 0 0 0 4 2 0 0 2 -0.076 -0.131 0.6501 0.9745 1 13385038 66483 Rpl36al 12 9 13 8 16 10 9 10 14 -0.076 -0.378 0.9336 0.9164 1 124301210 211660 Cspp1 0 0 1 0 0 0 0 0 0 -0.077 -0.097 0.6387 0.9948 0.9883 110625624 21454 Tcp1 1 1 3 3 7 1 2 4 4 -0.077 -0.186 0.6854 0.9479 1 241982820 240174 Thada 0 1 0 0 0 0 0 0 0 -0.078 -0.103 0.6401 0.9914 0.9917 117168301 16772 Lama1 0 0 0 0 0 0 0 1 0 -0.078 -0.105 0.6406 0.9896 0.9935 157909782 12785 Cnbp 5 4 4 3 7 3 5 4 5 -0.078 -0.243 0.7413 0.9297 1 226823367 14194 Fh1 5 9 8 6 11 5 5 9 10 -0.078 -0.322 0.8465 0.9179 1 9790247 56459 Sae1 0 0 0 0 1 0 0 0 0 -0.079 -0.105 0.6406 0.9896 0.9935 270288742 75725 Phf14 0 0 0 0 0 1 0 0 0 -0.079 -0.117 0.6444 0.9822 1 46395466 21753 Tes 0 0 0 0 0 0 0 0 1 -0.080 -0.107 0.6411 0.9888 0.9943 13277350 66317 Wdr61 0 1 0 0 1 0 0 0 0 -0.080 -0.107 0.6413 0.9880 0.9952 33620739 17904 Myl6 7 8 9 8 13 6 7 11 9 -0.080 -0.338 0.8705 0.9170 1 20330802 22041 Trf 25 18 33 14 42 17 23 27 31 -0.080 -0.582 1 0.9359 1 6680027 14661 Glud1 27 25 29 24 42 22 24 30 33 -0.080 -0.651 1 0.9457 1 45476577 16551 Kif11 0 0 0 0 1 0 0 0 0 -0.081 -0.108 0.6416 0.9880 0.995 327315368 234214 Sorbs2 0 0 0 0 1 0 0 0 0 -0.081 -0.111 0.6425 0.9863 0.997 124487362 99889 Arfip1 0 0 0 1 0 0 0 0 0 -0.081 -0.116 0.6443 0.9822 1 19527078 99571 Fgg 1 0 1 2 3 0 2 1 2 -0.081 -0.144 0.6567 0.9673 1 114158681 67931 Serpini2 36 31 36 29 53 32 31 36 37 -0.081 -0.723 1 0.9555 1 172072613 51797 Ctps 0 0 0 0 1 0 0 0 0 -0.082 -0.111 0.6425 0.9855 0.9978 23956138 66711 Sbds 0 0 0 0 1 0 0 0 1 -0.082 -0.122 0.6466 0.9791 1 225703070 73139 Cenpv 1 0 1 0 4 1 0 2 2 -0.082 -0.150 0.6600 0.9639 1 Page 61 of 73 Diabetes

6677785 19981 Rpl37a 7 6 8 6 14 6 7 8 9 -0.083 -0.343 0.8774 0.9168 1 149267855 677113 LOC677113 10 8 10 9 17 8 10 10 12 -0.083 -0.398 0.9650 0.9169 1 111120329 12843 Col1a2 13 13 10 9 12 9 11 8 14 -0.083 -0.401 0.9699 0.9170 1 13385374 271457 Rab5a 0 0 0 0 1 0 0 0 0 -0.084 -0.115 0.6437 0.9838 0.9996 17978276 140483 Hnmt 0 0 0 0 1 0 0 0 0 -0.084 -0.115 0.6439 0.9830 1 6678952 17768 Mthfd2 0 1 0 0 0 1 0 0 0 -0.084 -0.123 0.6470 0.9783 1 13384676 66044 Dtd1 0 0 0 0 1 0 0 0 0 -0.085 -0.126 0.6480 0.9767 1 58037481 76983 Scfd1 1 1 3 0 10 1 1 4 6 -0.085 -0.218 0.7146 0.9365 1 134031976 72416 Lrpprc 0 0 0 0 1 0 0 0 0 -0.087 -0.122 0.6464 0.9791 1 32130521 66244 Nemf 0 0 0 0 0 0 0 0 1 -0.087 -0.128 0.6488 0.9760 1 112363072 76709 Arpc2 0 2 2 2 6 1 2 3 4 -0.087 -0.206 0.7027 0.9407 1 149245407 100041098 Gm15431 1 2 1 0 3 1 1 2 2 -0.088 -0.158 0.6651 0.9600 1 21450129 110446 Acat1 14 15 16 12 27 15 14 13 20 -0.088 -0.516 1 0.9272 1 12963793 73626 1810009J06Rik 0 0 0 0 0 0 0 0 1 -0.089 -0.116 0.6441 0.9830 1 21312151 68953 Chmp2a 0 0 0 0 1 0 0 0 1 -0.089 -0.128 0.6488 0.9760 1 68989254 80985 Trim44 0 0 0 0 1 0 0 0 0 -0.089 -0.129 0.6492 0.9752 1 19527028 110611 Hdlbp 92 91 99 85 144 86 90 95 105 -0.089 -1.302 1 0.9985 0.8214 31543349 18195 Nsf 4 3 7 3 17 3 6 8 8 -0.090 -0.354 0.8950 0.9165 1 158533976 76577 Faf2 0 0 0 0 1 0 0 0 0 -0.091 -0.121 0.6458 0.9798 1 164663872 226352 Epb4.1l5 0 1 0 0 0 0 0 0 0 -0.091 -0.127 0.6484 0.9767 1 124358938 78887 Sfi1 0 0 0 0 0 0 1 0 0 -0.091 -0.129 0.6494 0.9752 1 133922586 71177 4933424B01Rik 0 0 0 0 0 0 1 0 0 -0.091 -0.132 0.6506 0.9737 1 6996917 14381 G6pdx 0 0 1 0 4 1 1 2 2 -0.091 -0.162 0.6675 0.9582 1 6679995 14598 Ggt1 12 15 17 9 28 12 15 17 15 -0.091 -0.538 1 0.9300 1 19527048 98758 Hnrnpf 0 3 1 0 6 2 2 3 2 -0.092 -0.207 0.7044 0.9398 1 149274885 100046684 LOC100046684 8 7 5 4 7 7 6 7 3 -0.092 -0.341 0.8749 0.9169 1 8394252 53421 Sec61a1 25 25 23 21 27 22 21 26 20 -0.092 -0.640 1 0.9443 1 269784766 211208 Gm382 0 0 0 0 0 0 0 1 0 -0.093 -0.126 0.6482 0.9767 1 18859587 66849 Ppp1r2 0 0 0 0 1 0 0 0 0 -0.093 -0.132 0.6509 0.9730 1 19526960 74143 Opa1 1 1 1 0 1 0 1 0 0 -0.094 -0.141 0.6552 0.9687 1 6756037 22629 Ywhah 1 0 2 3 6 1 1 3 5 -0.094 -0.232 0.7295 0.9324 1 14149635 11770 Fabp4 8 7 11 6 9 7 7 8 8 -0.094 -0.387 0.9474 0.9166 1 28173566 212503 Paox 1 0 1 0 1 1 0 0 1 -0.095 -0.130 0.6500 0.9745 1 115385966 238799 Tnpo1 0 1 0 0 1 0 0 1 1 -0.095 -0.134 0.6515 0.9723 1 160333613 381286 Serpinb3c 0 0 0 0 0 0 0 0 1 -0.095 -0.134 0.6517 0.9723 1 114205440 67671 Rpl38 12 12 12 11 16 11 10 12 13 -0.095 -0.461 1 0.9211 1 31981520 19752 Rnase1 24 24 26 24 45 21 26 28 30 -0.097 -0.749 1 0.9588 1 161353502 12406 Serpinh1 0 1 0 0 1 0 0 0 1 -0.098 -0.139 0.6543 0.9694 1 183396771 15510 Hspd1 27 32 35 26 51 24 28 33 40 -0.098 -0.818 1 0.9670 1 170671710 27059 Sh3d19 0 0 0 0 0 0 0 0 1 -0.099 -0.136 0.6529 0.9708 1 60592758 16439 Itpr2 0 0 0 0 1 0 0 0 0 -0.099 -0.142 0.6556 0.9680 1 13386010 68028 Rpl22l1 3 4 4 4 8 5 4 4 4 -0.100 -0.310 0.8290 0.9189 1 163965357 17938 Naca 3 4 6 3 9 2 3 6 7 -0.100 -0.331 0.8592 0.9174 1 27370092 233870 Tufm 12 16 20 11 22 10 11 16 22 -0.100 -0.574 1 0.9348 1 254540027 17449 Mdh1 17 21 18 24 25 15 18 20 24 -0.101 -0.664 1 0.9476 1 13195646 68337 Crip2 0 0 1 0 1 0 0 0 0 -0.102 -0.138 0.6538 0.9701 1 31560618 12237 Bub3 0 0 0 0 1 0 0 0 0 -0.102 -0.144 0.6570 0.9666 1 241666411 54483 Mefv 0 4 4 0 3 0 0 4 4 -0.102 -0.233 0.7301 0.9324 1 110625813 74840 Manf 24 25 26 21 33 20 24 23 26 -0.102 -0.755 1 0.9597 1 13385312 66905 Plin3 0 1 0 0 3 0 0 2 1 -0.103 -0.177 0.6787 0.9512 1 193788663 69019 Spcs1 4 4 4 3 5 3 3 4 4 -0.103 -0.307 0.8242 0.9193 1 209862915 12521 Cd82 0 0 0 0 1 0 0 0 0 -0.104 -0.145 0.6575 0.9666 1 153791270 226519 Lamc1 12 4 7 9 25 5 8 13 15 -0.104 -0.524 1 0.9283 1 170172520 13171 Dbt 12 18 16 11 33 12 15 20 19 -0.104 -0.654 1 0.9461 1 23956082 100503670 Rpl5 29 32 32 26 46 28 28 32 32 -0.104 -0.851 1 0.9705 1 13385294 66881 Pcyox1 1 2 0 0 3 0 0 0 3 -0.105 -0.189 0.6879 0.9464 1 33468857 15254 Hint1 7 6 10 6 8 7 6 7 7 -0.105 -0.433 1 0.9188 1 309266230 100047252 LOC100047252 10 15 14 10 24 10 10 15 18 -0.105 -0.572 1 0.9344 1 6677809 20104 Rps6 19 17 16 19 22 16 15 17 19 -0.105 -0.666 1 0.9478 1 110625886 71978 Ppp2r2a 0 0 0 0 1 0 0 0 0 -0.108 -0.150 0.6599 0.9639 1 21536262 71449 Mettl13 0 0 0 0 1 0 0 0 0 -0.108 -0.159 0.6655 0.9594 1 Diabetes Page 62 of 73

224967109 70231 Gorasp2 4 3 7 3 9 5 3 4 7 -0.108 -0.343 0.8774 0.9168 1 19527258 104776 Aldh6a1 31 31 35 26 47 27 29 31 34 -0.109 -0.887 1 0.9740 1 124486724 69191 Pdia2 121 139 149 106 193 108 114 132 157 -0.109 -1.769 0.7078 1 0.3789 183396792 12593 Cdyl 0 0 0 1 0 0 0 0 0 -0.110 -0.151 0.6607 0.9633 1 13385998 68015 Trap1 0 0 0 0 1 0 0 0 0 -0.110 -0.165 0.6696 0.9569 1 255003819 66676 Tmed7 0 0 0 0 1 1 0 0 0 -0.111 -0.168 0.6716 0.9552 1 236466498 320011 Uggt1 8 12 12 5 22 8 6 13 15 -0.111 -0.551 1 0.9317 1 121583922 15925 Ide 3 0 3 0 10 3 2 2 6 -0.112 -0.295 0.8070 0.9206 1 93102413 14635 Galk1 5 4 7 5 9 2 4 6 10 -0.112 -0.370 0.9200 0.9164 1 149251776 100046628 LOC100046628 9 7 8 10 10 9 7 9 7 -0.112 -0.496 1 0.9248 1 251823891 15115 Hars 6 9 8 7 24 6 6 10 17 -0.112 -0.533 1 0.9293 1 226874906 22627 Ywhae 15 15 23 18 29 15 16 18 23 -0.112 -0.689 1 0.9509 1 30794414 101861 Ints4 0 0 0 0 0 0 1 0 0 -0.114 -0.156 0.6641 0.9607 1 258547152 18571 Pdcd6ip 1 1 1 0 3 1 1 2 1 -0.114 -0.188 0.6868 0.9469 1 6680744 11933 Atp1b3 0 0 0 0 3 0 0 1 2 -0.114 -0.195 0.6927 0.9444 1 23956214 71514 Sfpq 2 1 3 0 4 0 0 4 2 -0.114 -0.250 0.7493 0.9282 1 125988403 76687 Spcs3 10 9 10 7 14 7 9 9 10 -0.114 -0.505 1 0.9257 1 22122625 227095 Hibch 9 11 13 9 10 5 7 10 15 -0.114 -0.546 1 0.9310 1 6679082 18107 Nmt1 1 1 1 1 6 1 1 3 2 -0.115 -0.224 0.7208 0.9349 1 6679299 18673 Phb 8 10 10 7 22 7 9 11 14 -0.115 -0.559 1 0.9328 1 226958653 19921 Rpl19 3 8 6 3 11 4 3 8 7 -0.116 -0.390 0.9527 0.9166 1 226823359 12847 Copa 23 26 30 23 52 19 22 30 38 -0.116 -0.901 1 0.9753 1 69724858 57257 Vav3 2 2 2 2 2 2 0 2 2 -0.117 -0.243 0.7411 0.9300 1 27754065 67895 Ppa1 3 2 3 4 9 1 2 6 6 -0.117 -0.333 0.8619 0.9173 1 251823978 18563 Pcx 9 7 14 10 34 11 8 14 19 -0.117 -0.641 1 0.9443 1 188035915 110695 Aldh7a1 18 22 18 17 43 15 19 24 25 -0.117 -0.792 1 0.9641 1 52353955 236539 Phgdh 35 37 42 35 49 31 32 37 42 -0.117 -1.049 1 0.9868 1 7305599 22139 Ttr 2 2 4 2 4 2 3 3 2 -0.118 -0.283 0.7906 0.9222 1 13195604 66475 Rps23 11 13 12 11 18 12 10 11 14 -0.118 -0.589 1 0.9370 1 147905039 382090 4922501C03Rik 2 2 2 2 3 2 2 2 2 -0.119 -0.246 0.7449 0.9291 1 31982511 11532 Adh5 3 1 1 0 5 1 1 2 4 -0.119 -0.251 0.7509 0.9279 1 124430537 109552 Sri 2 2 2 0 4 1 1 3 3 -0.119 -0.255 0.7555 0.9271 1 268838020 67873 Mri1 0 0 0 0 3 0 0 0 2 -0.121 -0.198 0.6956 0.9435 1 22122825 66713 Actr2 1 1 1 1 4 1 1 1 3 -0.121 -0.221 0.7177 0.9357 1 13385260 66834 Acot13 1 1 2 2 0 0 1 2 1 -0.122 -0.199 0.6966 0.9430 1 13385296 66882 Bzw1 3 4 6 2 6 2 3 6 4 -0.122 -0.361 0.9055 0.9164 1 22122387 107869 Cth 8 12 13 9 17 10 10 9 12 -0.122 -0.603 1 0.9388 1 118344452 66661 Srp72 11 15 19 12 31 10 12 20 21 -0.122 -0.730 1 0.9563 1 120407050 55989 Nop58 0 0 1 0 3 0 0 2 1 -0.124 -0.202 0.6993 0.9416 1 158853992 13806 Eno1 18 21 22 21 35 15 20 22 25 -0.124 -0.939 1 0.9786 1 255003709 230257 Rod1 0 0 1 0 1 0 0 0 0 -0.125 -0.159 0.6656 0.9594 1 28077049 75608 Chmp4b 1 1 0 1 3 1 0 0 2 -0.125 -0.214 0.7103 0.9381 1 114145493 56403 Syncrip 13 12 12 9 25 9 10 14 17 -0.125 -0.702 1 0.9527 1 12963569 66385 Ppp1r7 0 0 0 0 3 0 0 2 1 -0.126 -0.233 0.7304 0.9324 1 9256529 56050 Cyp39a1 3 2 3 2 4 3 4 2 1 -0.126 -0.318 0.8399 0.9182 1 21450263 228607 Mavs 0 0 0 0 0 0 0 0 1 -0.127 -0.178 0.6790 0.9512 1 149234330 100043257 Gm15453 2 1 2 1 0 1 1 1 2 -0.127 -0.203 0.7005 0.9411 1 244790045 59010 Sqrdl 1 3 3 2 9 1 2 5 5 -0.127 -0.353 0.8940 0.9165 1 13385942 12974 Cs 5 6 8 4 10 6 5 7 6 -0.127 -0.454 1 0.9205 1 38142460 110826 Etfb 20 22 20 14 23 15 18 18 19 -0.127 -0.800 1 0.9650 1 21624609 68021 Bphl 1 0 0 0 3 0 0 1 2 -0.128 -0.218 0.7150 0.9365 1 6678788 17155 Man1a 2 1 2 0 4 2 3 0 1 -0.128 -0.249 0.7481 0.9285 1 27370012 230709 Zmpste24 1 2 1 1 2 0 1 2 1 -0.129 -0.223 0.7194 0.9353 1 61651673 68292 Stt3b 0 1 2 2 5 1 1 1 5 -0.129 -0.270 0.7744 0.9243 1 58037465 76808 Rpl18a 16 18 16 18 27 16 16 16 19 -0.129 -0.828 1 0.9680 1 100817930 224090 Tmem44 0 0 0 0 0 0 0 1 0 -0.130 -0.184 0.6837 0.9485 1 13384618 14701 Gng12 3 2 2 1 4 2 2 2 3 -0.130 -0.290 0.8011 0.9211 1 13385572 67281 Rpl37 5 2 4 3 3 3 3 2 4 -0.130 -0.337 0.8685 0.9171 1 22122515 217737 Ahsa1 0 0 0 0 3 0 0 0 2 -0.131 -0.212 0.7092 0.9381 1 255958286 56451 Suclg1 10 5 7 6 11 4 7 7 10 -0.131 -0.522 1 0.9280 1 7305293 17829 Muc1 1 1 2 1 2 1 1 1 2 -0.132 -0.209 0.7062 0.9394 1 Page 63 of 73 Diabetes

9910314 56708 Clcf1 1 0 0 3 0 0 2 0 0 -0.132 -0.212 0.7084 0.9385 1 12313877 16619 Klk1b27 2 3 1 1 0 2 2 1 1 -0.132 -0.247 0.7465 0.9288 1 88758582 94184 Pdxdc1 0 0 2 0 2 1 0 2 0 -0.133 -0.222 0.7192 0.9353 1 58037109 68342 Ndufb10 1 3 4 3 9 2 3 3 6 -0.135 -0.392 0.9567 0.9167 1 283135194 170759 Atp13a1 6 5 12 5 19 5 7 11 10 -0.135 -0.601 1 0.9387 1 160707894 11677 Akr1b3 11 13 12 9 17 7 9 12 16 -0.135 -0.708 1 0.9535 1 9910548 56726 Sh3bgrl 2 0 1 0 2 0 2 1 1 -0.136 -0.212 0.7089 0.9385 1 18250284 67834 Idh3a 7 8 10 6 11 7 7 7 9 -0.136 -0.554 1 0.9321 1 26024336 57294 Rps27 11 10 14 11 17 8 10 13 13 -0.136 -0.681 1 0.9498 1 54607098 66945 Sdha 7 10 13 7 27 7 7 12 19 -0.137 -0.683 1 0.9501 1 262073041 69806 Slc39a11 0 0 0 0 2 0 0 1 1 -0.138 -0.206 0.7032 0.9403 1 31542438 66427 Cyb5b 0 3 4 0 8 3 3 0 5 -0.138 -0.360 0.9041 0.9164 1 21746145 69187 Erp27 22 24 23 16 26 18 19 20 21 -0.138 -0.939 1 0.9786 1 113680425 270076 Gcdh 0 0 0 0 4 0 0 0 3 -0.139 -0.255 0.7552 0.9271 1 31560731 11964 Atp6v1a 2 1 0 2 8 0 2 3 4 -0.139 -0.333 0.8622 0.9173 1 6755196 26441 Psma4 2 1 4 3 7 2 3 4 3 -0.139 -0.376 0.9302 0.9164 1 21489953 97114 Hist2h3c2 13 12 10 0 3 2 12 11 2 -0.139 -0.572 1 0.9344 1 6753620 13205 Ddx3x 12 15 14 11 28 13 14 13 16 -0.139 -0.789 1 0.9636 1 116089322 74142 Lonp1 0 0 1 0 3 0 0 2 1 -0.140 -0.230 0.7270 0.9331 1 240120054 110198 Akr7a5 4 1 2 1 2 0 2 1 3 -0.140 -0.281 0.7888 0.9224 1 13324684 66212 Sec61b 5 9 6 8 10 8 6 7 6 -0.140 -0.520 1 0.9276 1 13937391 14693 Gnb2 7 12 9 11 11 9 9 10 7 -0.140 -0.635 1 0.9435 1 339895744 12835 Col6a3 14 11 15 9 43 10 7 15 32 -0.141 -0.843 1 0.9696 1 309265053 100504912 LOC100504912 2 2 1 1 7 2 1 4 2 -0.143 -0.324 0.8496 0.9177 1 226958420 23970 Pacsin2 6 2 2 0 5 4 0 2 4 -0.143 -0.351 0.8896 0.9166 1 255522939 109785 Pgm3 0 1 0 0 3 0 1 2 1 -0.144 -0.235 0.7321 0.9320 1 309264759 545531 Gm5848 0 1 2 0 2 0 0 2 1 -0.144 -0.240 0.7378 0.9307 1 21539585 22272 Uqcrq 2 3 1 2 5 1 2 3 3 -0.144 -0.330 0.8577 0.9174 1 112807186 231659 Gcn1l1 2 5 2 0 36 2 4 9 17 -0.144 -0.625 1 0.9420 1 45504359 11973 Atp6v1e1 0 0 0 0 3 0 0 0 2 -0.145 -0.231 0.7281 0.9327 1 226443026 53605 Nap1l1 1 1 0 0 3 0 1 1 2 -0.145 -0.234 0.7314 0.9320 1 23956104 56248 Ak3 9 8 12 7 17 5 8 10 14 -0.145 -0.659 1 0.9469 1 6671549 11758 Prdx6 13 14 16 12 19 12 10 14 15 -0.145 -0.814 1 0.9665 1 18017605 93765 Ube2n 7 7 6 7 7 7 4 7 5 -0.146 -0.511 1 0.9267 1 7304875 11625 Ahsg 0 3 0 0 5 1 1 4 2 -0.147 -0.307 0.8241 0.9193 1 309265792 100504863 LOC100504863 6 6 6 6 8 5 5 6 6 -0.147 -0.546 1 0.9310 1 39930429 69276 Sec62 8 8 11 6 15 9 8 9 7 -0.148 -0.649 1 0.9454 1 31981945 22121 Rpl13a 26 24 28 25 32 20 21 25 27 -0.148 -1.086 1 0.9891 1 309265938 100504968 LOC100504968 0 0 0 0 3 0 0 1 2 -0.149 -0.246 0.7450 0.9291 1 21312175 68995 Mcts1 2 1 3 2 5 2 2 2 3 -0.149 -0.320 0.8431 0.9181 1 34328286 67680 Sdhb 4 7 5 6 14 4 6 8 7 -0.150 -0.571 1 0.9344 1 31982755 22352 Vim 25 23 31 28 47 23 26 27 30 -0.151 -1.199 1 0.9949 0.9206 6678281 21743 Inmt 1 0 0 0 2 0 0 0 0 -0.152 -0.250 0.7491 0.9282 1 119508439 66194 Pycrl 0 0 0 0 3 0 0 2 0 -0.152 -0.260 0.7613 0.9263 1 113205059 22608 Ybx1 1 3 2 4 3 0 4 1 3 -0.152 -0.347 0.8836 0.9167 1 227499103 215615 Rnpep 2 1 5 1 8 3 3 4 2 -0.152 -0.390 0.9534 0.9167 1 46593021 22273 Uqcrc1 11 13 15 10 20 8 8 14 17 -0.152 -0.794 1 0.9642 1 94721328 30960 Vapa 6 7 7 4 17 6 4 10 8 -0.154 -0.626 1 0.9422 1 6753262 12345 Capzb 6 5 8 7 11 4 5 8 8 -0.155 -0.624 1 0.9418 1 262118273 104458 Rars 9 8 11 7 26 6 7 15 14 -0.155 -0.764 1 0.9608 1 6679803 14225 Fkbp1a 1 1 3 1 4 1 1 2 3 -0.156 -0.305 0.8218 0.9194 1 283436218 216188 Aldh1l2 54 47 56 40 74 39 46 49 53 -0.156 -1.739 0.7553 1 0.4023 254826790 27376 Slc25a10 0 0 0 0 2 0 0 0 0 -0.157 -0.228 0.7245 0.9338 1 261824000 19167 Psma3 1 1 2 1 4 1 1 2 2 -0.158 -0.286 0.7952 0.9218 1 33563290 70152 Mettl7a1 5 6 4 4 10 3 5 5 7 -0.158 -0.512 1 0.9267 1 299758443 13179 Dcn 1 1 1 1 5 0 1 1 3 -0.159 -0.291 0.8018 0.9211 1 153945747 17837 Mug2 1 0 0 2 0 0 1 0 1 -0.160 -0.248 0.7467 0.9288 1 83627717 13684 Eif4e 2 3 2 2 4 2 2 3 2 -0.160 -0.349 0.8865 0.9166 1 30520239 320024 Nceh1 3 2 3 2 3 2 2 2 3 -0.160 -0.351 0.8899 0.9166 1 27734986 229709 Ahcyl1 0 1 1 1 9 0 2 5 0 -0.160 -0.362 0.9079 0.9164 1 6753322 12464 Cct4 3 5 5 2 18 3 3 8 9 -0.162 -0.589 1 0.9370 1 Diabetes Page 64 of 73

257096048 24068 Sra1 0 0 1 0 2 1 0 1 1 -0.163 -0.237 0.7342 0.9313 1 13385624 13665 Eif2s1 5 7 9 5 13 6 5 8 8 -0.164 -0.626 1 0.9422 1 6996913 12306 Anxa2 9 8 10 9 14 9 5 8 12 -0.164 -0.694 1 0.9516 1 9790141 56378 Arpc3 0 0 0 0 2 0 0 0 1 -0.166 -0.235 0.7329 0.9317 1 21539587 66091 Ndufa3 0 0 0 0 2 0 0 1 0 -0.166 -0.238 0.7355 0.9310 1 20149748 192166 Sardh 11 9 17 12 25 11 7 15 17 -0.166 -0.926 1 0.9776 1 21312580 70380 Mospd1 1 0 0 0 2 0 0 1 0 -0.167 -0.264 0.7665 0.9253 1 31542563 100037258 Dnajc3 19 26 22 14 32 16 19 20 22 -0.168 -1.147 1 0.9925 0.9668 6678225 21371 Tbca 1 1 3 0 1 1 2 1 1 -0.169 -0.281 0.7879 0.9226 1 227116345 26445 Psmb2 0 1 0 0 2 0 0 1 1 -0.172 -0.269 0.7724 0.9245 1 139948818 72722 Fam98a 0 0 0 0 2 0 0 0 0 -0.173 -0.252 0.7520 0.9276 1 19526814 17995 Ndufv1 4 5 5 2 12 2 4 7 6 -0.173 -0.578 1 0.9353 1 31981562 18746 Pkm2 28 24 33 24 47 21 24 28 32 -0.173 -1.431 1 1 0.6912 110625954 72900 Ndufv2 1 2 1 1 5 0 0 3 2 -0.174 -0.350 0.8882 0.9166 1 255003777 67201 Glod4 2 4 2 0 4 1 1 4 3 -0.175 -0.382 0.9402 0.9165 1 6753294 12385 Ctnna1 2 0 0 0 7 0 0 4 2 -0.176 -0.363 0.9095 0.9164 1 18250296 68193 Rpl24 13 17 18 17 18 12 15 14 15 -0.177 -1.020 1 0.9849 1 6755100 18813 Pa2g4 27 24 28 23 35 19 20 26 27 -0.177 -1.331 1 0.9993 0.7924 7106301 13589 Mapre1 0 0 0 0 2 0 0 0 0 -0.178 -0.253 0.753 0.9276 1 9845253 56258 Hnrnph2 0 0 0 0 2 0 0 0 0 -0.178 -0.260 0.762 0.9260 1 121674797 19063 Ppt1 1 1 0 0 2 0 1 1 0 -0.178 -0.265 0.768 0.9253 1 326633256 242235 Lrit3 0 0 3 1 4 0 0 4 0 -0.178 -0.334 0.864 0.9172 1 309264693 100504173 Gm15466 0 0 0 2 0 0 0 0 0 -0.179 -0.257 0.758 0.9268 1 6755402 20234 Sbp 0 2 0 0 0 0 0 0 0 -0.179 -0.261 0.763 0.9258 1 13385454 67092 Gatm 10 12 16 11 35 10 10 15 21 -0.180 -1.027 1 0.9854 1 114145505 15505 Hsph1 0 0 0 0 2 0 0 0 0 -0.181 -0.268 0.7715 0.9245 1 153791468 73112 3110003A17Rik 0 0 0 0 2 0 0 1 0 -0.181 -0.271 0.7753 0.9241 1 31980632 17035 Lxn 2 1 2 2 3 2 1 2 2 -0.181 -0.361 0.9054 0.9164 1 6680309 15528 Hspe1 9 8 13 12 16 9 8 10 12 -0.181 -0.851 1 0.9705 1 22165406 14618 Gjb1 0 0 1 0 2 0 0 1 1 -0.182 -0.269 0.7730 0.9243 1 21699068 69617 Pitrm1 0 0 0 0 2 0 0 0 0 -0.183 -0.276 0.7814 0.9232 1 117647249 16773 Lama2 7 3 4 3 17 6 2 6 9 -0.183 -0.686 1 0.9505 1 19527168 101739 Psip1 0 0 2 0 1 0 0 1 0 -0.184 -0.264 0.7666 0.9253 1 262231769 19655 Rbmx 0 0 0 1 2 0 1 1 1 -0.184 -0.273 0.7781 0.9236 1 46877109 108148 Galnt2 0 0 1 0 2 0 0 1 0 -0.184 -0.291 0.8016 0.9211 1 6753966 14555 Gpd1 2 2 2 0 6 3 2 2 2 -0.184 -0.411 0.9867 0.9175 1 160333837 54217 Rpl36 7 7 8 7 8 5 7 6 7 -0.184 -0.726 1 0.9560 1 13385310 66904 Pccb 9 12 13 5 31 4 7 15 21 -0.184 -0.952 1 0.9798 1 13384754 66142 Cox7b 1 0 0 0 2 0 0 1 0 -0.185 -0.280 0.7865 0.9228 1 13385322 66916 Ndufb7 1 1 1 1 3 1 1 1 2 -0.185 -0.296 0.8085 0.9204 1 31543974 54401 Ywhab 4 5 5 2 6 3 4 4 4 -0.185 -0.537 1 0.9298 1 6681183 13367 Diap1 0 1 1 0 2 1 0 1 1 -0.186 -0.291 0.8024 0.9209 1 6679573 19290 Pura 4 2 7 3 8 1 2 6 7 -0.186 -0.543 1 0.9307 1 6680806 12183 Bpgm 0 0 0 0 2 0 0 0 0 -0.188 -0.288 0.7981 0.9214 1 13385196 66736 Ttc35 0 0 0 0 2 0 0 0 1 -0.189 -0.280 0.7870 0.9226 1 256818776 212517 Wdr52 2 1 1 0 1 0 0 0 1 -0.190 -0.278 0.7846 0.9230 1 6753762 13849 Ephx1 2 2 2 2 4 2 2 2 2 -0.190 -0.396 0.9619 0.9169 1 38604071 103573 Xpo1 0 0 0 0 2 0 0 0 0 -0.191 -0.296 0.8081 0.9204 1 162138915 12896 Cpt2 1 2 0 0 4 0 0 1 3 -0.191 -0.350 0.8892 0.9166 1 21536248 103140 Gstt3 0 1 2 0 7 1 2 2 3 -0.191 -0.417 0.9977 0.9178 1 228008307 66052 Sdhc 0 0 0 0 2 0 0 0 0 -0.192 -0.279 0.7858 0.9228 1 164518942 13135 Dad1 5 7 6 5 8 6 5 6 4 -0.192 -0.691 1 0.9512 1 13386062 68117 Apool 0 0 0 0 2 0 0 0 0 -0.193 -0.268 0.7711 0.9248 1 11612505 64136 Sdf2l1 8 8 8 6 9 7 5 6 8 -0.193 -0.714 1 0.9544 1 22122615 226977 Actr1b 1 1 3 2 3 1 1 2 3 -0.194 -0.380 0.9363 0.9165 1 6755004 26926 Aifm1 3 4 2 2 7 3 1 3 5 -0.194 -0.526 1 0.9285 1 9789913 56447 Copz1 0 0 1 0 2 0 0 1 1 -0.195 -0.284 0.7919 0.9220 1 31981340 24070 Mpdu1 1 1 1 0 2 1 1 1 1 -0.195 -0.286 0.7950 0.9218 1 157951596 12349 Car2 1 3 2 1 9 1 4 2 4 -0.195 -0.484 1 0.9235 1 31982332 14645 Glul 0 0 2 1 0 0 1 0 0 -0.196 -0.297 0.8099 0.9203 1 117606345 16333 Ins1 2 2 2 2 4 2 2 2 2 -0.196 -0.412 0.9895 0.9175 1 Page 65 of 73 Diabetes

160707896 20901 Strap 1 1 1 0 5 1 1 2 2 -0.197 -0.369 0.9183 0.9164 1 27502349 66865 Pmpca 0 0 0 0 2 0 0 1 1 -0.198 -0.303 0.8181 0.9197 1 261878543 108156 Mthfd1 16 20 20 13 36 15 19 15 20 -0.198 -1.279 1 0.9979 0.8436 6679961 14489 Mtpn 0 0 1 0 2 0 0 1 1 -0.199 -0.283 0.7916 0.9222 1 18034682 14950 H13 8 6 9 7 11 6 7 7 7 -0.199 -0.775 1 0.9621 1 45544618 66902 Mtap 0 0 0 0 2 0 0 0 0 -0.200 -0.299 0.8125 0.9201 1 176865892 13682 Eif4a2 0 0 0 0 2 1 0 0 0 -0.200 -0.306 0.8222 0.9194 1 170172589 19153 Prx 3 0 0 0 3 0 0 3 0 -0.201 -0.366 0.9136 0.9164 1 31559926 225791 Zadh2 0 0 0 0 2 1 1 0 0 -0.202 -0.292 0.8031 0.9209 1 211065507 226414 Dars 12 8 16 11 29 8 8 15 18 -0.202 -1.071 1 0.9882 1 13385558 67264 Ndufb8 0 0 1 0 2 0 0 1 1 -0.203 -0.304 0.8205 0.9195 1 33469043 103425 Ncln 2 2 2 1 2 1 2 1 2 -0.203 -0.349 0.8864 0.9166 1 87116677 68944 Tmco1 2 2 2 1 5 2 2 2 2 -0.203 -0.423 1 0.9181 1 31543971 56418 Ykt6 1 1 1 1 2 1 1 1 1 -0.204 -0.293 0.8050 0.9207 1 268370181 56389 Stx5a 0 0 1 0 2 0 0 1 1 -0.204 -0.302 0.8169 0.9198 1 21312546 70186 Fam162a 0 0 0 0 2 0 0 0 0 -0.205 -0.298 0.8114 0.9203 1 157909797 53333 Tomm40 0 0 0 0 2 0 0 0 0 -0.205 -0.301 0.8156 0.9198 1 46309457 69568 Vkorc1l1 0 2 0 0 1 0 1 0 0 -0.205 -0.306 0.8232 0.9193 1 28076935 69654 Dctn2 0 0 0 0 2 0 0 0 1 -0.206 -0.288 0.7984 0.9214 1 117606383 67976 Trabd 0 0 0 0 2 0 0 0 0 -0.206 -0.316 0.8365 0.9184 1 26024309 231327 Ppat 0 0 0 0 2 0 0 0 1 -0.206 -0.320 0.8433 0.9181 1 31982089 223646 Naprt1 1 1 0 0 2 0 1 0 0 -0.207 -0.310 0.8285 0.9189 1 124301201 100978 Nfxl1 0 0 0 0 2 0 0 0 0 -0.207 -0.310 0.8291 0.9189 1 31560247 66314 Tpd52l2 0 1 0 0 2 0 1 0 0 -0.208 -0.304 0.8197 0.9195 1 241982740 17827 Mtx1 0 0 0 0 2 0 0 1 0 -0.209 -0.299 0.8132 0.9201 1 31980942 55980 Impa1 0 0 0 0 2 0 0 0 1 -0.209 -0.307 0.8244 0.9193 1 168693635 17939 Naga 0 0 1 0 2 0 0 0 1 -0.209 -0.312 0.8319 0.9188 1 21450325 233016 Blvrb 2 2 2 1 2 2 1 2 1 -0.209 -0.387 0.9470 0.9166 1 124486835 226562 Prrc2c 0 0 0 0 2 0 0 0 0 -0.210 -0.306 0.8230 0.9193 1 57634518 52398 40787 0 0 2 0 1 0 0 1 0 -0.210 -0.317 0.8384 0.9183 1 13385878 67804 Snx2 1 1 0 0 5 1 0 3 1 -0.210 -0.402 0.9719 0.9170 1 7710086 19325 Rab10 9 5 7 4 7 6 4 5 6 -0.210 -0.727 1 0.9560 1 9790145 56312 Nupr1 1 1 1 1 2 1 1 0 1 -0.211 -0.288 0.7975 0.9214 1 9790019 11886 Asah1 0 1 0 0 2 0 0 0 0 -0.211 -0.304 0.8203 0.9195 1 157951598 12334 Capn2 0 0 1 0 2 0 0 0 0 -0.211 -0.309 0.8267 0.9190 1 117956395 80877 Lrba 0 0 0 0 2 0 0 0 0 -0.211 -0.312 0.8307 0.9188 1 22122641 227737 Fam129b 1 0 2 0 0 0 0 1 0 -0.211 -0.340 0.8729 0.9169 1 33859560 14567 Gdi1 0 0 0 0 2 0 0 0 0 -0.212 -0.315 0.8364 0.9184 1 9845242 56358 Copz2 1 2 2 0 5 1 1 2 3 -0.212 -0.433 1 0.9188 1 21312062 68581 Tmed10 19 16 19 16 25 15 14 17 15 -0.212 -1.246 1 0.9968 0.875703 161484642 68316 Apoo 0 0 1 0 2 0 0 1 1 -0.213 -0.288 0.7974 0.9214 1 26986557 224045 Eif2b5 0 1 1 0 2 0 0 1 1 -0.213 -0.316 0.8371 0.9184 1 74271886 77951 Cyp20a1 0 0 0 0 2 0 0 0 1 -0.213 -0.330 0.8586 0.9174 1 254540154 69038 1810006K21Rik 0 2 2 0 3 1 0 2 2 -0.213 -0.373 0.9247 0.9164 1 255958247 53610 Nono 0 0 2 2 3 0 1 0 3 -0.213 -0.387 0.9472 0.9166 1 110350660 77006 Ddrgk1 2 3 2 2 5 2 2 2 3 -0.213 -0.500 1 0.9253 1 10946574 12709 Ckb 0 0 1 1 2 0 0 1 0 -0.214 -0.327 0.8528 0.9176 1 21312520 110391 Qdpr 4 3 5 3 10 3 3 4 6 -0.214 -0.642 1 0.9444 1 227908803 211548 Nomo1 3 4 7 3 5 4 3 4 4 -0.214 -0.684 1 0.9503 1 189339256 69047 Atp2c2 0 0 0 0 2 0 0 0 0 -0.216 -0.299 0.8134 0.9200 1 31981304 11972 Atp6v0d1 0 0 0 1 2 0 0 0 0 -0.216 -0.307 0.8235 0.9193 1 133504509 76303 Osbp 0 1 0 0 2 0 0 0 1 -0.216 -0.319 0.8411 0.9182 1 21314824 66144 Atp6v1f 0 0 0 0 2 0 0 0 0 -0.216 -0.325 0.8507 0.9177 1 34328278 66890 Lman2 3 3 7 3 11 3 3 5 7 -0.216 -0.717 1 0.9548 1 224967104 67996 Srsf6 0 0 2 0 0 0 0 0 0 -0.217 -0.299 0.8132 0.9201 1 357933645 77219 Ptgr2 0 1 1 0 2 1 1 1 1 -0.217 -0.305 0.8214 0.9194 1 77812697 22138 Ttn 0 0 0 0 2 0 0 0 0 -0.217 -0.339 0.8723 0.9169 1 247269929 13884 Ces1c 2 1 1 1 4 2 2 1 0 -0.217 -0.398 0.9657 0.9169 1 6754090 14873 Gsto1 1 2 2 1 6 0 0 2 4 -0.217 -0.493 1 0.9245 1 124248572 22327 Vbp1 0 0 0 0 2 0 0 0 0 -0.218 -0.333 0.8619 0.9173 1 77917602 28018 Ubfd1 0 0 1 0 2 0 0 0 1 -0.218 -0.337 0.8679 0.9171 1 Diabetes Page 66 of 73

9790159 56305 Pitpnb 0 0 0 0 3 0 0 2 1 -0.218 -0.340 0.8737 0.9169 1 188497698 245945 Rbm47 0 0 0 0 2 0 0 0 0 -0.219 -0.322 0.8459 0.9179 1 30425358 270906 Prr11 0 0 1 2 1 0 0 0 0 -0.219 -0.325 0.8510 0.9177 1 21312298 108037 Shmt2 8 5 12 2 15 4 6 9 8 -0.219 -0.838 1 0.9692 1 255003793 27370 Rps26 9 9 10 12 15 8 8 8 12 -0.219 -0.986 1 0.9824 1 6753136 11927 Atox1 1 1 0 0 2 0 1 0 0 -0.220 -0.315 0.8356 0.9185 1 13386060 52700 Txndc17 0 1 0 0 2 0 0 1 1 -0.220 -0.340 0.8725 0.9169 1 227908823 108147 Atic 0 1 0 0 10 0 0 2 5 -0.220 -0.509 1 0.9264 1 54292135 11593 Aga 2 0 0 0 1 0 1 0 0 -0.222 -0.326 0.8522 0.9176 1 21312550 71998 Slc25a35 2 1 3 2 6 2 3 2 2 -0.222 -0.500 1 0.9253 1 226529455 29856 Smtn 2 0 0 1 0 0 0 0 1 -0.223 -0.351 0.8898 0.9166 1 7304963 29876 Clic4 2 1 2 1 3 1 1 2 2 -0.223 -0.424 1 0.9182 1 6754036 14719 Got2 11 11 14 11 24 9 11 12 14 -0.223 -1.206 1 0.9953 0.9133 165377181 107271 Yars 19 21 24 17 35 16 18 19 22 -0.223 -1.518 1 1 0.6037 227499242 66663 Uba5 1 2 1 0 12 3 2 3 3 -0.224 -0.547 1 0.9310 1 33859751 216344 Rab21 0 0 0 0 2 0 0 0 0 -0.226 -0.302 0.8176 0.9197 1 31560705 14081 Acsl1 0 0 0 0 2 0 0 0 0 -0.226 -0.323 0.8470 0.9179 1 21704066 109905 Rap1a 6 6 9 6 7 5 5 6 6 -0.226 -0.836 1 0.9689 1 13385168 66694 Uqcrfs1 5 7 10 7 16 7 5 7 10 -0.226 -0.988 1 0.9826 1 7949005 11957 Atp5j 6 4 7 7 7 4 5 5 6 -0.227 -0.792 1 0.9641 1 31542956 53323 Ube2k 0 0 0 0 2 1 0 0 1 -0.228 -0.331 0.8595 0.9173 1 158635992 54132 Pdlim1 0 0 0 1 7 1 0 3 2 -0.229 -0.443 1 0.9196 1 172088112 72397 Rbm12b 0 0 0 2 0 0 0 0 0 -0.230 -0.328 0.8543 0.9176 1 86439977 26450 Rbbp9 0 0 0 0 2 0 0 0 0 -0.230 -0.338 0.8703 0.9170 1 21313138 76263 Gstk1 0 0 0 0 2 0 0 0 0 -0.230 -0.342 0.8766 0.9168 1 6755472 378702 Serf2 1 1 1 0 2 1 1 0 0 -0.230 -0.354 0.8943 0.9165 1 40254595 12934 Dpysl2 0 0 1 0 2 0 0 0 0 -0.231 -0.335 0.8656 0.9171 1 31981983 20866 Stim1 0 0 0 0 2 0 0 0 0 -0.231 -0.337 0.8679 0.9171 1 13384730 66118 Sarnp 0 1 0 0 2 1 1 1 1 -0.231 -0.348 0.8851 0.9167 1 33859809 110135 Fgb 6 3 5 4 4 3 4 4 3 -0.231 -0.715 1 0.9544 1 10946678 13495 Drg2 0 0 0 0 2 0 0 0 1 -0.232 -0.313 0.8322 0.9186 1 237757339 241158 Ankmy1 0 0 2 0 0 0 0 0 0 -0.232 -0.354 0.8945 0.9165 1 153792449 53322 Nucb2 7 7 10 5 14 5 6 8 8 -0.232 -1.004 1 0.9837 1 269973915 268566 Gphn 0 0 1 0 2 0 0 0 1 -0.233 -0.346 0.8819 0.9167 1 261862339 19652 Rbm3 0 0 0 0 2 0 0 0 0 -0.234 -0.327 0.8528 0.9176 1 13507632 80880 Kank3 2 0 0 0 0 0 0 0 0 -0.234 -0.329 0.8564 0.9175 1 255958156 18749 Prkacb 0 0 1 0 2 0 0 0 0 -0.234 -0.343 0.8771 0.9168 1 55741460 57320 Park7 6 7 10 4 17 7 5 7 9 -0.234 -0.967 1 0.9809 1 12963737 110750 Cse1l 0 0 1 0 2 0 0 0 1 -0.235 -0.344 0.8794 0.9168 1 83921621 97998 Deptor 0 0 0 0 2 0 0 0 0 -0.235 -0.345 0.8814 0.9167 1 153792526 104303 Arl1 1 1 1 1 2 0 1 1 1 -0.235 -0.349 0.8870 0.9166 1 6755252 19291 Purb 1 1 2 0 4 0 0 0 3 -0.235 -0.439 1 0.9193 1 21704144 232087 Mat2a 1 1 0 0 5 2 0 2 0 -0.235 -0.452 1 0.9203 1 154350209 209837 Slc38a5 6 6 6 3 9 5 3 5 6 -0.235 -0.790 1 0.9638 1 124248568 23881 G3bp2 0 0 1 0 2 0 0 0 1 -0.236 -0.352 0.8925 0.9165 1 31982233 67154 Mtdh 3 2 2 0 4 1 1 3 3 -0.236 -0.476 1 0.9227 1 162329564 53872 Caprin1 0 0 0 0 2 0 0 0 0 -0.237 -0.339 0.8721 0.9169 1 8394460 50875 Tmod3 0 0 0 0 2 0 0 0 0 -0.237 -0.344 0.8797 0.9167 1 29789195 70533 Btf3l4 1 1 1 0 2 1 1 1 1 -0.238 -0.358 0.9014 0.9164 1 170650724 18624 Pepd 0 0 0 0 2 0 0 0 0 -0.239 -0.349 0.8864 0.9166 1 29126205 52538 Acaa2 5 10 8 5 16 4 4 6 14 -0.239 -0.966 1 0.9808 1 85861182 11668 Aldh1a1 10 11 11 6 22 9 10 14 5 -0.239 -1.180 1 0.9941 0.9387 13385042 66488 Fam136a 0 0 1 0 2 0 0 0 0 -0.240 -0.337 0.8683 0.9171 1 10946936 11636 Ak1 0 1 1 0 2 1 1 0 1 -0.241 -0.347 0.8842 0.9167 1 166851844 71653 4930506M07Rik 0 0 0 0 2 0 0 0 0 -0.241 -0.348 0.8857 0.9166 1 158631225 13664 Eif1a 0 0 0 2 0 0 0 0 0 -0.242 -0.349 0.8865 0.9166 1 16716395 93684 42248 0 0 1 0 2 0 1 0 1 -0.242 -0.360 0.9039 0.9164 1 170295832 13601 Ecm1 0 0 0 2 0 0 0 0 0 -0.242 -0.372 0.9236 0.9164 1 13385268 109672 Cyb5 5 5 5 5 8 3 5 5 5 -0.242 -0.729 1 0.9563 1 226958601 224139 Golgb1 0 0 0 0 2 0 0 0 0 -0.244 -0.342 0.8757 0.9168 1 33859558 14470 Rabac1 1 0 2 0 1 1 1 1 1 -0.245 -0.363 0.9095 0.9164 1 Page 67 of 73 Diabetes

20982845 233908 Fus 0 0 0 0 2 0 1 1 0 -0.246 -0.358 0.9009 0.9164 1 189458847 319876 Cobll1 1 0 2 0 0 0 1 1 0 -0.247 -0.353 0.8937 0.9165 1 260763915 77038 Arfgap2 0 0 0 0 2 0 0 0 0 -0.247 -0.372 0.9229 0.9164 1 6678551 22318 Vamp2 0 0 2 0 1 0 0 0 1 -0.247 -0.384 0.9425 0.9165 1 21450071 12411 Cbs 33 36 34 27 45 23 27 31 28 -0.247 -1.994 0.4278 0.9978 0.2406 27228985 66414 Ndufa12 1 2 2 1 2 1 1 1 2 -0.248 -0.400 0.9694 0.9170 1 16930823 114863 Prosc 0 0 0 0 2 0 0 0 0 -0.250 -0.374 0.9263 0.9164 1 13384768 66155 Ufc1 2 2 2 2 5 2 2 2 2 -0.250 -0.542 1 0.9305 1 160298168 14467 Gbas 4 3 5 4 11 3 2 6 6 -0.250 -0.837 1 0.9690 1 6755114 54683 Prdx5 4 5 5 5 13 4 5 6 5 -0.250 -0.902 1 0.9753 1 13385134 66624 Spcs2 10 12 12 18 14 9 9 10 12 -0.250 -1.225 1 0.9960 0.895902 225579041 233913 BC017158 0 0 0 1 2 0 0 0 0 -0.251 -0.386 0.9460 0.9166 1 40068491 67040 Ddx17 0 0 0 2 0 0 0 0 0 -0.251 -0.393 0.9576 0.9168 1 17933768 76238 Grhpr 7 7 6 5 13 5 6 6 7 -0.251 -0.948 1 0.9795 1 91064867 245474 Dkc1 0 0 0 0 2 0 0 0 1 -0.252 -0.366 0.9144 0.9164 1 6678085 20703 Serpina1d 1 1 1 0 2 0 0 0 0 -0.252 -0.374 0.9260 0.9164 1 13385678 67458 Ergic1 3 5 7 3 12 3 3 8 5 -0.252 -0.853 1 0.9707 1 229892316 227197 Ndufs1 8 9 9 7 17 3 4 13 11 -0.252 -1.059 1 0.9874 1 46049022 66413 Psmd6 0 0 0 0 2 0 0 0 0 -0.254 -0.370 0.9200 0.9164 1 46309573 20338 Sel1l 1 1 2 0 1 1 1 1 1 -0.254 -0.376 0.9297 0.9164 1 257467604 333433 Gpd1l 1 1 2 0 3 1 2 1 1 -0.254 -0.405 0.9775 0.9172 1 171846276 27384 Akr1c13 0 0 0 0 2 0 0 0 0 -0.255 -0.378 0.9332 0.9164 1 247269309 12764 Cmas 0 0 0 0 4 0 0 2 0 -0.256 -0.441 1 0.9194 1 269973935 71832 Csl 1 0 0 1 2 1 1 0 1 -0.257 -0.384 0.9426 0.9165 1 21703888 217715 Eif2b2 0 0 0 0 2 0 0 1 1 -0.258 -0.368 0.9164 0.9164 1 171543837 14360 Fyn 0 0 0 0 2 0 0 0 0 -0.259 -0.380 0.9360 0.9165 1 13384766 66154 Tmem14c 0 0 0 0 2 0 0 0 0 -0.259 -0.387 0.9483 0.9166 1 19526994 76890 Memo1 0 0 0 0 2 0 0 0 0 -0.260 -0.373 0.9247 0.9164 1 17505218 66092 Ghitm 1 0 0 0 2 0 0 1 1 -0.260 -0.377 0.9316 0.9164 1 281485611 218490 Btf3 0 0 0 0 2 0 0 1 0 -0.261 -0.388 0.9501 0.9166 1 21313234 66898 Baiap2l1 2 0 0 0 0 0 0 0 1 -0.261 -0.398 0.9663 0.9169 1 9789873 56307 Metap2 1 1 2 1 6 0 0 1 4 -0.262 -0.538 1 0.9300 1 6679263 18598 Pdha2 0 0 2 0 0 1 0 0 0 -0.263 -0.375 0.9281 0.9164 1 37574048 66152 Uqcr10 1 1 1 1 2 1 0 1 1 -0.263 -0.388 0.9495 0.9166 1 6755210 23997 Psmd13 1 0 2 0 6 1 1 2 3 -0.263 -0.522 1 0.9280 1 124339838 15482 Hspa1l 0 0 0 0 2 0 0 0 0 -0.264 -0.406 0.9791 0.9173 1 6753484 12833 Col6a1 2 2 2 6 12 2 1 4 8 -0.264 -0.810 1 0.9660 1 27370510 269823 Pon3 2 1 2 1 7 1 1 3 3 -0.265 -0.550 1 0.9316 1 70909327 12848 Cops2 0 0 0 0 2 0 0 0 1 -0.266 -0.351 0.8909 0.9166 1 20137008 12111 Bgn 1 2 0 0 1 0 0 1 1 -0.266 -0.385 0.9444 0.9166 1 264681505 83813 Tnk1 2 0 0 0 0 0 0 0 0 -0.266 -0.395 0.9607 0.9168 1 309265963 623286 Gm6415 1 2 2 2 0 1 1 2 0 -0.266 -0.453 1 0.9205 1 118150668 14977 Slc39a7 3 3 3 2 6 2 2 3 4 -0.266 -0.669 1 0.9481 1 255958292 56454 Aldh18a1 11 16 16 12 31 7 13 20 13 -0.266 -1.562 1 1 0.5597 31542602 15568 Elavl1 0 2 0 0 1 0 0 0 1 -0.268 -0.414 0.9921 0.9177 1 27369581 78830 Slc25a12 1 2 1 2 10 0 1 4 4 -0.268 -0.660 1 0.9470 1 283135110 270685 Mthfd1l 2 0 0 0 0 0 0 0 0 -0.269 -0.439 1 0.9192 1 18390323 68365 Rab14 5 8 8 5 13 9 5 5 5 -0.269 -1.018 1 0.9847 1 112807195 12859 Cox5b 15 14 15 10 13 9 6 11 15 -0.269 -1.355 1 0.9998 0.7685 34328379 52815 Ldhd 0 0 0 0 2 0 0 1 1 -0.270 -0.405 0.9776 0.9172 1 31560239 66514 Asrgl1 0 0 0 0 2 0 0 0 0 -0.271 -0.417 0.9974 0.9178 1 13195690 78294 Rps27a 5 6 7 5 13 4 6 6 6 -0.271 -1.018 1 0.9847 1 110625998 67838 Dnajb11 11 10 12 11 19 7 10 11 11 -0.272 -1.361 1 0.9999 0.7619 74229034 233726 Ipo7 0 1 2 0 0 0 0 1 0 -0.273 -0.375 0.9279 0.9164 1 91206392 110119 Mpi 0 0 0 0 2 0 0 1 0 -0.274 -0.399 0.9681 0.9170 1 110347491 11500 Adam7 1 0 0 0 2 0 0 0 0 -0.274 -0.403 0.9740 0.9171 1 116256512 11991 Hnrnpd 3 3 1 0 2 3 0 1 1 -0.274 -0.497 1 0.9250 1 67906177 20334 Sec23a 0 3 2 1 4 0 0 0 4 -0.274 -0.510 1 0.9265 1 120537241 107045 Lars 5 12 11 9 35 7 6 16 16 -0.274 -1.387 1 1 0.7352 160298213 14782 Gsr 1 0 1 1 2 0 0 1 1 -0.275 -0.392 0.9557 0.9167 1 61676179 18796 Plcb2 2 1 2 0 2 0 0 0 2 -0.277 -0.451 1 0.9203 1 Diabetes Page 68 of 73

85701810 229722 5330417C22Rik 0 0 0 0 2 0 0 0 0 -0.278 -0.420 1 0.9180 1 377834351 233637 Gm4887 0 0 1 0 2 1 1 1 0 -0.278 -0.431 1 0.9187 1 229608928 170760 Acbd3 0 0 0 0 2 0 0 0 0 -0.279 -0.413 0.9900 0.9176 1 6678329 21817 Tgm2 3 4 2 1 14 3 2 3 7 -0.279 -0.829 1 0.9682 1 65301464 13196 Asap1 0 0 0 0 2 0 0 0 1 -0.280 -0.436 1 0.9190 1 166295210 69601 Dab2ip 0 0 0 0 2 0 0 0 0 -0.282 -0.397 0.9637 0.9169 1 30519943 68653 Samm50 1 0 0 0 2 0 0 0 0 -0.283 -0.409 0.9839 0.9174 1 312836854 76257 Slc38a3 2 1 3 0 1 1 1 2 0 -0.284 -0.513 1 0.9268 1 54020676 229317 Eif2a 3 0 3 1 10 1 1 4 5 -0.284 -0.732 1 0.9567 1 111119010 109815 H47 0 0 0 0 2 0 0 0 0 -0.285 -0.425 1 0.9183 1 40789280 14084 Faf1 0 0 1 0 2 0 0 0 0 -0.286 -0.412 0.9892 0.9175 1 6681071 13014 Cstb 1 2 3 1 3 2 1 2 1 -0.286 -0.508 1 0.9262 1 16506279 94214 Spock2 0 0 0 0 2 1 0 0 0 -0.287 -0.420 1 0.9180 1 160358819 11722 Amy1 7 0 7 3 3 2 4 2 5 -0.287 -0.822 1 0.9675 1 13507622 83493 Sacm1l 5 6 6 5 9 4 1 6 8 -0.287 -0.980 1 0.9820 1 85662379 233724 Tmem41b 1 2 1 0 3 1 1 2 0 -0.288 -0.509 1 0.9264 1 56711244 407785 Ndufs6 0 0 0 0 6 0 0 0 3 -0.288 -0.551 1 0.9317 1 9055370 54709 Eif3i 6 4 8 5 12 6 3 4 8 -0.288 -1.028 1 0.9854 1 134053905 69077 Psmd11 1 1 2 0 8 2 2 2 2 -0.289 -0.623 1 0.9418 1 21536222 66481 Rps21 13 8 16 11 16 9 10 10 9 -0.289 -1.423 1 1 0.6978 188497724 15191 Hdgf 2 1 3 4 5 2 2 3 2 -0.292 -0.684 1 0.9503 1 149263103 621837 Gm6265 4 6 5 5 5 5 3 3 4 -0.293 -0.849 1 0.9703 1 188219551 13667 Eif2b4 0 0 0 0 2 0 0 0 0 -0.294 -0.427 1 0.9185 1 21313144 67059 Ola1 7 8 9 8 13 7 5 7 8 -0.296 -1.187 1 0.9944 0.9315 125628629 55944 Eif3d 3 4 2 4 10 1 3 6 4 -0.297 -0.887 1 0.9740 1 31981106 57377 Mogs 2 5 5 4 19 4 3 7 7 -0.297 -1.024 1 0.9851 1 6681115 13113 Cyp3a13 0 0 0 0 2 0 0 0 0 -0.302 -0.422 1 0.9181 1 119372300 56298 Atl2 0 0 0 0 2 0 1 0 1 -0.302 -0.461 1 0.9211 1 83921612 105245 Txndc5 1 1 0 1 7 2 1 2 2 -0.303 -0.611 1 0.9400 1 86439984 94279 Sfxn2 1 0 1 1 4 0 0 0 2 -0.305 -0.522 1 0.9280 1 7657067 50527 Ero1l 0 0 0 0 2 0 0 0 0 -0.306 -0.437 1 0.9191 1 13385800 67673 Tceb2 2 2 2 0 3 2 1 2 1 -0.307 -0.545 1 0.9309 1 6679583 19326 Rab11b 0 0 0 0 4 0 0 0 2 -0.308 -0.518 1 0.9273 1 6753498 12857 Cox4i1 9 11 13 9 17 7 9 9 10 -0.309 -1.399 1 1 0.7232 31981086 27984 Efhd2 1 1 2 0 3 1 1 2 1 -0.313 -0.532 1 0.9291 1 13937355 13885 Esd 4 6 6 3 15 4 5 5 6 -0.314 -1.114 1 0.9907 0.9956 21313679 71679 Atp5h 6 7 6 5 15 3 5 6 9 -0.314 -1.190 1 0.9945 0.9291 124487457 78283 Mtap7d2 0 2 2 0 2 1 0 0 2 -0.316 -0.520 1 0.9276 1 6755578 20587 Smarcb1 2 0 0 1 3 0 0 0 2 -0.317 -0.524 1 0.9281 1 16716499 94280 Sfxn3 2 1 1 0 5 0 0 0 3 -0.318 -0.591 1 0.9372 1 13385652 67427 Rps20 11 9 13 20 15 9 10 10 11 -0.321 -1.573 1 1 0.5495 6680690 11757 Prdx3 7 7 9 5 16 5 5 7 9 -0.322 -1.269 1 0.9976 0.8539 113722131 269254 Setx 0 2 0 1 1 1 0 1 0 -0.324 -0.452 1 0.9203 1 254540162 110821 Pcca 16 18 25 15 35 9 16 17 21 -0.326 -1.960 0.4580 0.9983 0.2581 13386026 68045 2700060E02Rik 1 2 3 1 3 2 1 2 1 -0.330 -0.623 1 0.9418 1 7305061 30795 Fkbp3 4 2 4 2 5 1 3 2 4 -0.330 -0.815 1 0.9667 1 84794552 23980 Pebp1 3 4 4 2 9 3 1 4 5 -0.335 -0.935 1 0.9782 1 115511018 22284 Usp9x 0 0 0 0 2 0 0 0 0 -0.337 -0.497 1 0.9250 1 6754910 18221 Nudc 2 1 3 2 2 1 1 2 2 -0.339 -0.626 1 0.9422 1 188528894 68059 Tm9sf2 0 0 0 1 3 0 0 0 0 -0.341 -0.526 1 0.9285 1 158186704 76936 Hnrnpm 0 2 3 2 8 2 1 3 3 -0.341 -0.804 1 0.9654 1 8394027 51792 Ppp2r1a 2 3 6 4 11 1 4 4 6 -0.341 -1.046 1 0.9866 1 30424613 229905 Ccbl2 1 0 0 0 3 1 1 1 0 -0.342 -0.507 1 0.9260 1 145966883 59029 Psmd14 0 0 0 0 3 0 0 1 1 -0.346 -0.556 1 0.9323 1 255759902 17161 Maoa 0 0 0 0 3 0 0 0 1 -0.347 -0.523 1 0.9280 1 88014720 16211 Kpnb1 0 1 0 0 6 1 1 2 2 -0.347 -0.659 1 0.9469 1 6724311 11522 Adh1 0 2 3 2 6 2 3 2 1 -0.349 -0.800 1 0.9650 1 19527358 28000 Prpf19 1 1 0 0 3 1 0 1 0 -0.352 -0.573 1 0.9348 1 31982223 16779 Lamb2 0 0 0 3 0 0 0 0 0 -0.353 -0.524 1 0.9281 1 58037125 68563 Dpm3 0 1 1 2 2 1 1 1 1 -0.353 -0.536 1 0.9297 1 12963539 66071 Ethe1 0 0 0 0 3 0 0 0 0 -0.353 -0.547 1 0.9310 1 Page 69 of 73 Diabetes

356995868 53817 Ddx39b 2 0 2 1 3 0 0 0 2 -0.354 -0.626 1 0.9420 1 257796245 235339 Dlat 6 6 9 6 15 6 5 6 7 -0.355 -1.365 1 1 0.7579 18700024 170718 Idh3b 1 1 4 1 9 3 3 1 2 -0.358 -0.860 1 0.9713 1 6680854 12389 Cav1 2 4 5 3 5 3 2 2 4 -0.358 -0.927 1 0.9777 1 6753086 11792 Apex1 0 0 0 0 3 0 0 0 0 -0.360 -0.536 1 0.9297 1 22203747 12834 Col6a2 4 1 2 3 8 2 2 3 3 -0.361 -0.947 1 0.9793 1 118601017 13191 Dctn1 0 0 0 0 3 0 0 0 0 -0.362 -0.537 1 0.9298 1 214010153 235606 Apeh 0 1 1 0 3 0 0 0 1 -0.363 -0.535 1 0.9295 1 75677435 11671 Aldh3a2 3 1 2 2 6 0 2 2 3 -0.363 -0.761 1 0.9603 1 18152793 68263 Pdhb 4 7 11 7 15 3 4 8 10 -0.363 -1.364 1 1 0.7579 9910482 56018 Stard10 1 1 1 0 3 1 1 0 0 -0.364 -0.555 1 0.9321 1 19111162 107358 Tm9sf3 1 1 3 2 7 2 1 2 3 -0.364 -0.758 1 0.9600 1 29150272 110379 Sec13 3 4 4 4 10 2 5 4 3 -0.368 -1.125 1 0.9914 0.9858 21703762 98221 Eif3m 0 0 0 0 3 1 1 0 1 -0.369 -0.556 1 0.9324 1 116268115 11992 Auh 0 0 0 0 3 0 0 0 1 -0.369 -0.583 1 0.9361 1 7110703 19184 Psmc5 3 2 2 0 10 3 0 3 3 -0.371 -0.903 1 0.9755 1 157041244 17910 Myo15 0 3 0 0 0 0 1 0 0 -0.372 -0.535 1 0.9297 1 31981273 66054 Cndp2 2 0 3 2 10 2 2 1 5 -0.372 -0.924 1 0.9773 1 226437665 69875 Ndufa11 0 0 1 0 3 0 0 0 0 -0.374 -0.569 1 0.9341 1 6753494 23789 Coro1b 0 0 0 0 3 0 0 0 0 -0.374 -0.569 1 0.9342 1 21312044 73830 Eif3k 1 1 2 1 4 1 1 1 2 -0.374 -0.637 1 0.9437 1 13385434 67054 Paics 0 0 2 0 4 2 0 1 0 -0.374 -0.682 1 0.9500 1 229608938 14688 Gnb1 0 0 4 0 5 0 0 0 4 -0.375 -0.748 1 0.9588 1 6680345 15929 Idh3g 1 0 1 0 3 0 0 1 0 -0.377 -0.544 1 0.9307 1 84794548 227620 Uap1l1 2 2 3 1 8 2 2 1 4 -0.377 -0.868 1 0.9721 1 34419622 230721 Pabpc4 33 37 36 28 35 21 24 23 26 -0.378 -2.916 0.0192 0.9929 0.0059 27369748 214579 Aldh5a1 0 0 2 0 2 0 1 1 1 -0.379 -0.566 1 0.9337 1 61097906 109711 Actn1 0 3 5 1 26 3 3 3 11 -0.379 -1.292 1 0.9982 0.8318 22122499 217140 Scrn2 1 0 0 0 3 0 0 0 0 -0.380 -0.589 1 0.9370 1 21426893 56702 Hist1h1b 3 2 4 4 5 2 3 1 4 -0.380 -0.913 1 0.9764 1 256773209 77605 H2afv 4 5 4 2 3 3 2 2 3 -0.381 -0.964 1 0.9806 1 227330590 67490 1810074P20Rik 6 8 12 7 20 5 5 8 11 -0.381 -1.681 0.8474 1 0.4504 6753960 14544 Gda 0 0 1 0 3 0 0 1 1 -0.383 -0.561 1 0.9332 1 31542413 23790 Coro1c 0 2 0 0 2 0 0 0 0 -0.383 -0.610 1 0.9398 1 21539599 66576 Uqcrh 3 1 0 0 1 0 0 0 0 -0.384 -0.590 1 0.9370 1 124487331 109778 Blvra 0 0 0 0 3 0 0 0 0 -0.384 -0.608 1 0.9396 1 6681079 13030 Ctsb 1 0 2 0 4 0 0 2 1 -0.384 -0.676 1 0.9492 1 21728376 67938 Myl12b 0 0 0 0 7 0 3 0 0 -0.386 -0.740 1 0.9577 1 22128627 20322 Sord 8 7 12 10 18 7 6 8 9 -0.386 -1.702 0.8137 1 0.4324 253314540 212307 Mapre2 0 0 1 1 3 0 0 0 0 -0.387 -0.596 1 0.9379 1 7305581 30055 Timm13 2 1 2 0 3 1 0 1 2 -0.387 -0.661 1 0.9472 1 149255313 100043508 Gm9769 0 1 1 0 3 1 1 1 1 -0.388 -0.557 1 0.9324 1 21312159 68969 Eif1b 0 0 0 0 3 0 0 1 1 -0.388 -0.610 1 0.9398 1 23956078 27407 Abcf2 1 1 0 0 3 1 0 0 1 -0.389 -0.603 1 0.9388 1 172072657 56737 Alg2 0 0 1 0 3 0 0 1 1 -0.389 -0.615 1 0.9405 1 19527388 107260 Otub1 0 0 0 0 3 0 0 0 0 -0.390 -0.573 1 0.9348 1 148747408 16775 Lama4 0 0 0 0 3 0 0 0 0 -0.391 -0.568 1 0.9339 1 31980840 53869 Rab11a 4 3 2 3 0 2 2 2 0 -0.391 -0.859 1 0.9713 1 158518433 65970 Lima1 1 0 1 0 3 0 0 0 1 -0.393 -0.603 1 0.9388 1 124486867 67048 Vma21 0 0 0 0 3 0 0 0 0 -0.394 -0.569 1 0.9341 1 377834662 100862648 LOC100862648 0 0 0 0 3 0 0 0 0 -0.394 -0.587 1 0.9366 1 8393988 54128 Pmm2 1 0 1 1 3 0 0 0 1 -0.395 -0.607 1 0.9396 1 31981830 12866 Cox7a2 5 4 5 6 6 4 3 3 4 -0.395 -1.116 1 0.9909 0.9935 165972315 66922 Rras2 0 0 0 0 3 0 0 0 1 -0.396 -0.620 1 0.9413 1 33859722 72736 Tmx1 1 0 1 1 3 0 0 1 1 -0.399 -0.610 1 0.9398 1 197333728 664994 Isoc2a 0 1 0 0 5 1 0 0 2 -0.400 -0.674 1 0.9489 1 9790055 56428 Mtch2 0 0 1 0 3 0 0 0 0 -0.402 -0.618 1 0.9411 1 21704140 58875 Hibadh 1 0 2 1 4 0 0 2 1 -0.403 -0.672 1 0.9485 1 34610207 234734 Aars 5 8 11 4 20 6 3 6 11 -0.403 -1.595 0.9749 1 0.5281 112293275 17075 Epcam 0 0 0 0 3 0 0 0 0 -0.405 -0.585 1 0.9364 1 161484634 12846 Comt 1 0 1 0 3 0 0 1 0 -0.405 -0.653 1 0.9459 1 Diabetes Page 70 of 73

112181167 12261 C1qbp 0 0 1 1 5 1 1 1 2 -0.406 -0.734 1 0.9570 1 238231384 19175 Psmb6 2 3 2 1 5 2 1 1 3 -0.408 -0.837 1 0.9690 1 228480251 18000 37500 0 0 0 0 3 0 0 0 0 -0.410 -0.641 1 0.9443 1 13385726 67530 Uqcrb 3 2 3 3 4 1 1 3 3 -0.412 -0.862 1 0.9716 1 31982856 13382 Dld 10 9 11 7 23 5 6 10 11 -0.413 -1.878 0.5511 0.9994 0.3045 157951743 14979 H2-Ke6 0 0 0 0 3 0 0 0 0 -0.414 -0.599 1 0.9383 1 6679505 19185 Psmd4 0 0 0 0 3 0 0 1 0 -0.415 -0.629 1 0.9426 1 83816893 13207 Ddx5 2 0 4 0 9 0 0 4 3 -0.415 -1.023 1 0.9851 1 13384938 66366 Ergic3 3 2 2 0 5 2 1 0 3 -0.416 -0.875 1 0.9729 1 124378050 227648 Sec16a 2 2 2 0 6 2 1 2 2 -0.417 -0.884 1 0.9738 1 145966915 286940 Flnb 3 3 6 3 13 3 2 3 7 -0.417 -1.328 1 0.9992 0.7950 6755714 21345 Tagln 4 2 5 2 9 3 2 2 5 -0.418 -1.170 1 0.9936 0.9470 15147224 14057 Sfxn1 6 5 9 7 14 3 4 7 8 -0.418 -1.562 1 1 0.5597 126116563 80903 Fgf16 0 0 0 0 3 0 0 0 0 -0.419 -0.624 1 0.9418 1 225543420 228359 Arhgap1 1 0 0 1 7 0 2 1 2 -0.419 -0.819 1 0.9670 1 225543400 52430 Echdc2 2 2 2 0 6 1 1 1 4 -0.419 -0.842 1 0.9696 1 254692911 207352 Sec23ip 0 0 0 0 3 0 0 0 0 -0.420 -0.657 1 0.9465 1 110347469 11287 Pzp 6 8 8 3 14 4 8 3 6 -0.420 -1.497 1 1 0.6234 300192993 13418 Dnajc1 1 1 2 0 2 1 1 1 0 -0.421 -0.618 1 0.9411 1 124486885 242274 Lrrc7 0 0 0 0 3 0 0 0 0 -0.421 -0.625 1 0.9420 1 18700032 67628 Anp32b 3 0 0 0 0 0 0 0 1 -0.421 -0.635 1 0.9435 1 149266669 100041273 Gm3244 1 2 1 0 4 1 1 1 2 -0.421 -0.671 1 0.9485 1 15808988 22384 Eif4h 4 3 2 2 6 3 1 2 3 -0.421 -0.972 1 0.9812 1 126518317 12266 C3 4 3 3 2 0 0 2 3 1 -0.422 -0.858 1 0.9712 1 19111164 170930 Sumo2 1 1 2 1 2 1 1 1 1 -0.423 -0.650 1 0.9456 1 83921618 22350 Ezr 3 1 3 2 2 2 0 0 2 -0.423 -0.790 1 0.9638 1 8567402 20383 Srsf3 0 3 0 2 6 4 0 0 0 -0.423 -0.817 1 0.9667 1 61743961 66395 Ahnak 2 1 3 4 7 2 1 3 3 -0.426 -0.994 1 0.9830 1 27369583 78895 Pus7l 0 0 3 0 0 0 0 0 0 -0.428 -0.653 1 0.9461 1 18252782 11905 Serpinc1 3 0 2 0 4 0 0 0 3 -0.430 -0.808 1 0.9659 1 225543103 212647 Aldh4a1 2 1 4 2 8 2 2 3 2 -0.438 -1.065 1 0.9878 1 34328400 110809 Srsf1 3 1 3 0 3 1 0 1 3 -0.440 -0.854 1 0.9708 1 134053947 30948 Bin1 0 0 0 0 3 0 0 1 0 -0.441 -0.691 1 0.9512 1 6753882 14228 Fkbp4 2 2 1 0 7 1 1 1 4 -0.444 -0.920 1 0.9770 1 116734870 16993 Lta4h 5 2 4 4 16 2 3 4 7 -0.444 -1.377 1 1 0.7459 31543942 22330 Vcl 0 0 6 0 10 0 0 4 4 -0.446 -1.163 1 0.9933 0.9529 6753670 13480 Dpm1 1 0 1 0 7 0 0 1 3 -0.452 -0.836 1 0.9689 1 30425250 238880 Actbl2 0 0 0 0 3 0 0 0 0 -0.456 -0.731 1 0.9567 1 148747546 20714 Serpina3k 7 5 14 8 17 4 7 6 9 -0.456 -1.955 0.4635 0.9983 0.2609 254939582 76483 Lmf1 0 1 0 0 4 0 1 0 0 -0.463 -0.739 1 0.9577 1 113195678 16783 Lamp1 2 2 2 2 2 1 1 1 2 -0.465 -0.775 1 0.9621 1 19527378 68539 Tmem109 0 3 3 0 3 1 2 2 1 -0.466 -0.839 1 0.9693 1 186700620 72039 Mccc1 3 6 10 4 19 3 1 6 11 -0.477 -1.805 0.6522 1 0.3521 229608895 98386 Lbr 0 0 0 0 3 0 0 0 1 -0.485 -0.699 1 0.9523 1 170650601 107227 Macrod1 1 3 1 1 4 1 1 0 2 -0.486 -0.871 1 0.9725 1 21313668 71881 2310001A20Rik 0 1 1 1 4 0 1 1 1 -0.490 -0.743 1 0.9580 1 6679465 19089 Prkcsh 3 5 4 2 8 2 1 4 4 -0.492 -1.306 1 0.9986 0.8174 161484662 319195 Rpl17 23 23 23 17 2 18 23 0 0 -0.492 -2.719 0.0829 0.9936 0.0154 31982522 11409 Acads 2 1 2 0 6 0 0 2 2 -0.494 -0.975 1 0.9816 1 298676450 69225 Carkd 1 4 3 0 7 2 1 3 2 -0.501 -1.085 1 0.9890 1 227499238 14651 Hagh 2 0 1 0 5 1 0 0 2 -0.503 -0.833 1 0.9686 1 19526912 70356 St13 2 1 4 4 9 1 0 4 4 -0.505 -1.260 1 0.9973 0.8616 6754632 26413 Mapk1 0 0 0 0 6 0 0 0 2 -0.506 -0.863 1 0.9717 1 254588110 14957 Hist1h1d 0 0 0 5 6 4 0 0 0 -0.507 -1.105 1 0.9903 1 226437587 12827 Col4a2 0 0 0 0 4 0 0 0 1 -0.509 -0.808 1 0.9659 1 13384788 80280 Cdk5rap3 2 1 3 0 11 1 1 3 4 -0.514 -1.242 1 0.9966 0.8808 20270267 20324 Sdpr 0 0 0 3 2 0 0 0 1 -0.516 -0.827 1 0.9680 1 244791124 75221 Dpp3 3 5 3 2 7 2 3 4 0 -0.521 -1.352 1 0.9997 0.7712 163310776 11774 Ap3b1 0 0 0 0 4 0 0 0 0 -0.522 -0.779 1 0.9625 1 157951676 11807 Apoa2 1 1 2 3 1 1 0 0 1 -0.522 -0.801 1 0.9651 1 6680722 11844 Arf5 0 2 1 1 3 1 1 1 1 -0.522 -0.822 1 0.9675 1 Page 71 of 73 Diabetes

46849708 20916 Sucla2 6 5 8 4 16 5 2 6 6 -0.522 -1.887 0.5397 0.9993 0.2989 31542273 230866 C230096C10Rik 0 0 0 0 4 1 0 1 0 -0.524 -0.852 1 0.9705 1 13384696 66059 Krtcap2 0 2 1 0 3 0 0 1 1 -0.525 -0.832 1 0.9685 1 118150658 17988 Ndrg1 0 0 0 0 4 0 0 0 0 -0.527 -0.832 1 0.9685 1 19527256 104721 Ddx1 5 3 6 2 17 3 2 5 6 -0.527 -1.658 0.8829 1 0.4700 22122695 231872 Aimp2 0 3 2 1 7 0 2 2 2 -0.528 -1.061 1 0.9876 1 226530266 327799 Usp44 2 0 2 1 2 0 0 1 0 -0.529 -0.809 1 0.9660 1 22122539 223453 Dap 1 1 1 2 3 1 1 1 1 -0.529 -0.834 1 0.9687 1 283945572 26914 H2afy 0 0 0 0 4 0 0 0 0 -0.530 -0.866 1 0.9720 1 46195430 225887 Ndufs8 1 1 2 2 4 1 1 1 2 -0.530 -0.946 1 0.9792 1 21312950 75406 Ndufs7 0 0 0 0 4 1 0 1 0 -0.532 -0.836 1 0.9689 1 45504394 16412 Itgb1 0 2 0 0 3 0 1 0 1 -0.533 -0.825 1 0.9678 1 13386100 68202 Ndufa5 2 1 1 1 5 1 1 2 1 -0.534 -0.960 1 0.9803 1 171543883 18073 Nid1 6 1 4 6 16 2 0 3 10 -0.535 -1.694 0.8268 1 0.4391 12963591 66592 Stoml2 1 0 0 0 4 0 0 0 0 -0.537 -0.821 1 0.9673 1 257196228 109731 Maob 0 0 1 0 4 0 1 1 1 -0.538 -0.828 1 0.9680 1 149275191 100047577 LOC100047577 3 0 0 4 0 0 0 2 0 -0.539 -0.950 1 0.9795 1 18266680 67041 Oxct1 0 0 2 1 3 0 0 0 1 -0.542 -0.805 1 0.9654 1 39573709 52009 Hn1l 0 0 2 0 3 0 1 1 1 -0.542 -0.882 1 0.9735 1 8394347 53416 Stk39 1 0 0 0 4 1 0 1 1 -0.544 -0.808 1 0.9659 1 110347473 11808 Apoa4 1 0 0 0 4 1 0 1 1 -0.544 -0.825 1 0.9678 1 148747424 11739 Slc25a4 0 0 4 0 1 0 0 0 0 -0.548 -0.836 1 0.9690 1 21312626 71955 2400003C14Rik 0 0 2 0 3 1 0 1 1 -0.549 -0.808 1 0.9659 1 29789148 66218 Ndufb9 0 0 0 0 4 0 0 1 1 -0.549 -0.819 1 0.9670 1 154240730 216705 Clint1 0 2 1 1 5 1 0 2 1 -0.559 -0.976 1 0.9817 1 7242156 26394 Lypla2 1 0 1 0 4 0 0 0 0 -0.560 -0.876 1 0.9729 1 113930699 12288 Cacna1c 0 0 0 0 4 0 0 0 1 -0.565 -0.880 1 0.9734 1 13384756 66143 Eef1e1 1 2 0 0 3 0 0 0 1 -0.565 -0.900 1 0.9752 1 224922803 14571 Gpd2 0 1 0 0 4 0 0 0 0 -0.566 -0.906 1 0.9758 1 238814391 12468 Cct7 2 3 3 2 9 1 3 4 1 -0.566 -1.376 1 1 0.7472 110224442 50493 Txnrd1 0 0 0 0 4 0 0 0 1 -0.567 -0.887 1 0.9740 1 22550094 19087 Prkar2a 2 1 3 1 1 1 1 0 1 -0.571 -0.872 1 0.9726 1 153791464 100101806 Srp54c 0 0 0 4 0 0 0 0 0 -0.576 -0.881 1 0.9734 1 356995942 21787 Tfg 2 4 3 3 8 2 1 3 3 -0.577 -1.409 1 1 0.7125 183979966 15530 Hspg2 8 6 7 10 17 5 3 4 10 -0.577 -2.083 0.3664 0.9966 0.1984 357527382 14874 Gstz1 0 2 0 0 3 0 1 1 0 -0.578 -0.918 1 0.9768 1 61657921 16573 Kif5b 0 0 0 0 6 0 1 1 2 -0.581 -0.964 1 0.9807 1 33563256 14679 Gnai3 3 3 3 3 3 3 2 1 1 -0.581 -1.263 1 0.9974 0.8591 260304980 545091 Gm5803 0 2 0 3 0 0 0 0 0 -0.586 -0.908 1 0.9759 1 31981425 83768 Dpp7 1 0 3 1 7 1 1 1 3 -0.586 -1.178 1 0.9940 0.9399 31543113 18826 Lcp1 0 2 3 0 8 1 1 2 3 -0.587 -1.273 1 0.9977 0.8487 161016793 13209 Ddx6 1 0 2 0 3 0 1 1 1 -0.613 -0.966 1 0.9808 1 31981269 30926 Glrx3 1 1 1 0 5 1 1 1 1 -0.613 -1.021 1 0.9849 1 254692859 66108 Ndufa9 1 1 1 1 5 1 1 1 0 -0.614 -1.003 1 0.9836 1 227116358 26922 Mecr 1 6 7 0 8 0 2 3 4 -0.617 -1.572 1 1 0.5508 31982171 17836 Mug1 0 0 4 0 2 0 0 0 0 -0.618 -1.042 1 0.9863 1 160358829 15458 Hpx 5 3 2 1 11 2 1 3 4 -0.620 -1.570 1 1 0.5521 7305577 30058 Timm8a1 1 1 1 0 5 1 0 1 0 -0.625 -1.040 1 0.9862 1 6678449 22117 Tst 1 0 2 1 13 1 2 2 3 -0.627 -1.397 1 1 0.7245 22122523 218138 Gmds 3 2 5 6 13 3 2 5 3 -0.630 -1.824 0.6242 1 0.3393 27229283 104444 Rexo2 1 2 0 0 4 0 0 0 0 -0.631 -0.977 1 0.9818 1 124487356 99100 Cep152 1 0 2 0 9 0 0 0 3 -0.631 -1.175 1 0.9939 0.942303 161086971 12340 Capza1 0 0 0 0 5 0 0 0 1 -0.637 -1.011 1 0.9842 1 110347487 11428 Aco1 2 1 4 1 10 1 1 2 4 -0.639 -1.439 1 1 0.6831 309266590 434434 Gm5621 2 3 2 2 2 1 1 0 2 -0.645 -1.170 1 0.9936 0.9470 118197277 14118 Fbn1 12 6 16 13 28 6 7 7 12 -0.648 -2.973 0.0137 0.9927 0.0045 377834874 100862258 LOC100862258 0 3 3 0 6 3 0 0 0 -0.650 -1.251 1 0.9970 0.8706 20149754 192169 Ufsp2 0 0 1 1 5 0 0 1 1 -0.653 -1.087 1 0.9892 1 228008337 19182 Psmc3 0 2 1 0 6 0 1 1 2 -0.654 -1.157 1 0.9930 0.9587 90903233 625249 Gpx4 0 2 3 3 5 0 2 0 2 -0.655 -1.298 1 0.9984 0.8253 42741690 66589 Ube2v1 0 0 0 0 5 0 0 0 0 -0.656 -1.078 1 0.9886 1 Diabetes Page 72 of 73

13385392 108124 Napa 3 4 4 1 11 0 2 3 4 -0.657 -1.611 0.9523 1 0.5132 158631246 104130 Ndufb11 2 2 1 1 3 1 1 1 1 -0.661 -1.138 1 0.9920 0.9758 124487211 110351 Rap1gap 0 0 0 0 5 0 0 1 1 -0.668 -1.053 1 0.9871 1 22128805 259087 Olfr622 0 0 2 0 4 0 0 0 0 -0.671 -1.125 1 0.9914 0.9858 7242197 19170 Psmb1 0 0 0 0 5 0 0 0 0 -0.676 -1.021 1 0.9849 1 21312012 68375 Ndufa8 0 2 0 1 9 0 1 1 3 -0.681 -1.364 1 1 0.7592 227498710 66116 Cml1 2 2 3 2 5 2 0 0 2 -0.687 -1.358 1 0.9999 0.7645 168480106 22763 Zfr 4 0 0 0 2 1 0 0 0 -0.691 -1.060 1 0.9875 1 14389431 20867 Stip1 2 3 4 1 9 1 2 3 2 -0.692 -1.640 0.9099 1 0.4865 188219589 16906 Lmnb1 1 2 4 1 4 1 0 0 2 -0.702 -1.283 1 0.9980 0.8397 309263856 100504629 Gm17669 0 0 0 6 0 0 0 0 0 -0.710 -1.134 1 0.9919 0.9781 110625656 18569 Pdcd4 3 0 0 1 4 0 0 0 0 -0.731 -1.175 1 0.9939 0.9423 281485615 17993 Ndufs4 1 2 4 0 4 1 1 1 2 -0.733 -1.298 1 0.9984 0.8253 210031252 218865 Chdh 0 2 4 2 11 1 2 2 3 -0.734 -1.619 0.9401 1 0.5059 28173550 235072 39326 0 0 0 0 6 0 0 0 0 -0.736 -1.218 1 0.9957 0.9034 167716841 5912284 ATP8 4 2 4 3 4 1 1 2 3 -0.736 -1.575 1 1 0.5470 13385518 67166 Arl8b 2 1 3 1 3 0 1 0 1 -0.737 -1.235 1 0.9964 0.8858 242332572 29875 Iqgap1 1 0 2 0 5 0 0 0 1 -0.748 -1.147 1 0.9925 0.9679 114326497 16777 Lamb1 5 1 0 4 17 0 0 4 5 -0.752 -2.009 0.4153 0.9976 0.2334 10946942 59022 Edf1 2 3 6 0 6 1 2 3 1 -0.767 -1.749 0.7398 1 0.3941 40353220 12040 Bckdhb 1 1 4 1 3 0 1 1 1 -0.768 -1.295 1 0.9984 0.8279 31980703 30956 Aass 3 0 4 1 4 1 2 0 0 -0.774 -1.398 1 1 0.7245 12963497 16644 Kng1 1 2 0 2 4 1 1 0 0 -0.785 -1.221 1 0.9958 0.9009 298676496 67075 Magt1 1 0 3 2 3 1 1 1 1 -0.792 -1.233 1 0.9963 0.8884 118344444 544963 Iqgap2 0 1 0 0 9 1 1 1 2 -0.813 -1.482 1 1 0.6393 100817933 229211 Acad9 0 1 3 0 5 0 0 1 1 -0.840 -1.354 1 0.9998 0.7699 31560517 26451 Rpl27a 0 0 0 7 0 0 0 0 0 -0.841 -1.383 1 1 0.7392 119433657 621893 Hist2h2ab 0 7 0 0 0 0 0 0 0 -0.857 -1.447 1 1 0.6738 12963633 67184 Ndufa13 3 0 4 2 4 1 1 2 1 -0.867 -1.513 1 1 0.6090 51092303 386551 Gm5409 0 0 0 7 0 0 0 0 0 -0.877 -1.427 1 1 0.6938 117553604 104158 Ces1d 1 6 5 2 10 1 3 2 2 -0.915 -2.168 0.3314 0.9957 0.1618 13385584 67307 Pbld2 9 10 11 7 10 5 8 0 1 -0.930 -2.977 0.0134 0.9927 0.0044 73622267 78038 Mccc2 4 5 5 2 12 2 2 3 2 -0.948 -2.356 0.3019 0.9945 0.0880 183396774 12039 Bckdha 1 2 4 0 8 0 0 0 2 -1.017 -1.891 0.5348 0.9992 0.2965 18087805 16898 Rps2 0 0 9 0 0 0 0 0 0 -1.025 -1.656 0.8864 1 0.4723 19705424 22123 Psmd3 0 1 1 0 9 0 1 1 1 -1.030 -1.813 0.6402 1 0.3466 149254294 100046223 LOC100046223 0 0 0 9 0 0 0 0 0 -1.049 -1.745 0.7458 1 0.3971 125347376 192176 Flna 1 0 0 1 10 0 1 1 0 -1.106 -1.840 0.6016 0.9999 0.3287 31982861 12350 Car3 0 6 2 0 4 0 1 1 0 -1.111 -1.893 0.5321 0.9992 0.2957 116805315 226499 BC003331 1 2 3 2 6 1 0 0 1 -1.112 -1.887 0.5398 0.9993 0.2997 6678087 20704 Serpina1e 0 3 0 0 9 0 0 1 1 -1.162 -2.012 0.4132 0.9976 0.2322 149251263 100042355 Gm10705 3 0 5 4 10 3 0 0 0 -1.170 -2.348 0.3028 0.9945 0.0907 161484668 19046 Ppp1cb 0 0 3 0 9 0 0 0 0 -1.175 -2.016 0.4099 0.9975 0.2302 6680618 11364 Acadm 2 4 3 1 5 0 0 1 1 -1.205 -2.086 0.3649 0.9966 0.1972 21450149 209027 Pycr1 7 2 10 6 18 2 1 5 2 -1.243 -3.459 0.0014 0.9917 0.0003 45592934 19353 Rac1 0 0 0 4 9 0 0 0 0 -1.301 -2.091 0.3621 0.9965 0.1949 294712564 665433 Hist1h2ao 2 0 3 10 1 0 1 0 1 -1.325 -2.107 0.3547 0.9964 0.1885 6755893 22074 Try4 47 0 26 12 0 0 0 0 0 -3.010 -5.553 0 0.9912 0 Control (PBS) Treatment (Ex-4) Page 73 of 73 Diabetes

Supplementary Table 2. Summary of proteomics data for Amylase and Lipase and islet-associated proteins.

Spectral counts Control (PBS) Treatment (Ex-4) Log Fold ProteinID Gene ID Gene Name S1 S2 S3 S4 S5 S6 S7 S8 S9 Change Zstatistic FDR FDRup FDRdown 298676467 545562 Amy2b 0 0 0 0 2 0 0 109 0 3.247 7.114 0 0 0.9920 111607467 109959 Amy2a5 150 176 170 193 180 63 186 139 87 0.061 1.183 1 0.5169 1 160358819 11722 Amy1 7 2 0 4 7 2 5 3 3 -0.287 -0.822 1 0.9675 1

9256628 18946 Pnliprp1 66 70 70 68 65 70 73 51 92 0.021 0.274 1 1 0.9057 160333869 18947 Pnliprp2 30 31 29 28 28 31 33 25 39 0.021 0.178 0.8975 1 0.8985 13591860 54473 Tollip 0 0 0 0 0 0 0 0 1 -0.045 -0.058 0.6356 1 0.9642 37674236 69060 Pnlip 73 73 84 74 84 80 99 61 136 -0.072 -0.953 1 0.9798 1

6678035 20604 Sst 0 0 1 0 1 0 0 0 0 -0.027 -0.039 0.6383 1 0.9534 33468853 14526 Gcg 0 2 1 1 3 0 0 3 2 0.044 0.083 0.7281 1 0.9084 117606345 16333 Ins1 2 2 2 2 4 2 2 2 2 -0.196 -0.412 0.9895 0.9175 1